rs397507553

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong

The NM_000135.4(FANCA):​c.3788_3790delTCT​(p.Phe1263del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000102 in 1,613,544 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

FANCA
NM_000135.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:19O:1

Conservation

PhyloP100: 5.09
Variant links:
Genes affected
FANCA (HGNC:3582): (FA complementation group A) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]
ZNF276 (HGNC:23330): (zinc finger protein 276) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in kinetochore. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000135.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 16-89740841-GAGA-G is Pathogenic according to our data. Variant chr16-89740841-GAGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 41003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89740841-GAGA-G is described in Lovd as [Pathogenic]. Variant chr16-89740841-GAGA-G is described in Lovd as [Pathogenic]. Variant chr16-89740841-GAGA-G is described in Lovd as [Likely_pathogenic]. Variant chr16-89740841-GAGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FANCANM_000135.4 linkc.3788_3790delTCT p.Phe1263del disruptive_inframe_deletion Exon 38 of 43 ENST00000389301.8 NP_000126.2 O15360-1
ZNF276NM_001113525.2 linkc.*2603_*2605delGAA 3_prime_UTR_variant Exon 11 of 11 ENST00000443381.7 NP_001106997.1 Q8N554-1I6L9I3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FANCAENST00000389301.8 linkc.3788_3790delTCT p.Phe1263del disruptive_inframe_deletion Exon 38 of 43 1 NM_000135.4 ENSP00000373952.3 O15360-1
ZNF276ENST00000443381.7 linkc.*2603_*2605delGAA 3_prime_UTR_variant Exon 11 of 11 1 NM_001113525.2 ENSP00000415836.2 Q8N554-1

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152092
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.0000997
AC:
25
AN:
250632
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135502
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000159
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000103
AC:
150
AN:
1461334
Hom.:
0
AF XY:
0.000105
AC XY:
76
AN XY:
726922
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000115
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.0000920
AC:
14
AN:
152210
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74416
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.0000245
Hom.:
0
Bravo
AF:
0.000132
EpiCase
AF:
0.000164
EpiControl
AF:
0.000178

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:19Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Fanconi anemia complementation group A Pathogenic:9
Dec 24, 2019
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NM_000135.2(FANCA):c.3788_3790delTCT(F1263del) is classified as pathogenic in the context of Fanconi anemia complementation group A. Sources cited for classification include the following: PMID 24584348, 17924555 and 19367192. Classification of NM_000135.2(FANCA):c.3788_3790delTCT(F1263del) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Feb 28, 2020
Leiden Open Variation Database
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: curation

Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Daniela Pilonetto, Johan de Winter, Sue Richards. -

Sep 22, 2022
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 16, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 11, 2022
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Mar 30, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 11, 2024
Human Genetics Section, Sidra Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

Franklin and VarSome were utilized as supplementary tools to predict the pathogenicity of the identified variant. The patient exhibited the following symptoms: Skin: Café-au-lait spots Malformations: ischiopubic synchondroses asymmetry (normal variant) Head: Microcephaly Growth retardation: below 5th centile Consequently, Whole Genome Sequencing (WGS) was performed, which identified the variant responsible for the observed phenotypes. We are currently preparing the publication detailing these findings, and the PubMed ID (PMID) will be provided upon its release. -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 31, 2023
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PM2 supporting, PM3 very strong, PM4 -

Fanconi anemia Pathogenic:5
Dec 08, 2017
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This inframe deletion of a single amino acid has been reported as a homozygous and compound heterozygous change in individuals with Fanconi Anemia from ethnically diverse populations (PMID: 9371798, 21273304, 20301575). The highest allele frequency in the ExAC and gnomAD population databases is 0.03% with no reported homozygotes. Based on the available evidence, c.3788_3790delTCT (p. Phe1263del) is classified as pathogenic. -

Feb 01, 2018
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 06, 2021
Sema4, Sema4
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Dec 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant, c.3788_3790del, results in the deletion of 1 amino acid(s) of the FANCA protein (p.Phe1263del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs397507553, gnomAD 0.02%). This variant has been observed in individual(s) with Fanconi anemia (FA) (PMID: 9371798, 15643609, 21273304, 21659346). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects FANCA function (PMID: 21273304). For these reasons, this variant has been classified as Pathogenic. -

Apr 05, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: FANCA c.3788_3790delTCT (p.Phe1263del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant allele was found at a frequency of 0.0001 in 250632 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in FANCA causing Fanconi Anemia (0.0001 vs 0.0022), allowing no conclusion about variant significance. c.3788_3790delTCT has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Fanconi Anemia (e.g. Castella_2011, Pilonetto_2017). These data indicate that the variant is very likely to be associated with disease. Eleven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:4
Jul 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

FANCA: PM3:Strong, PM2, PM4, PS3:Moderate -

Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 03, 2022
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The frequency of this variant in the general population, 0.00017 (6/35374 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in the homozygous or compound heterozygous state in many individuals with Fanconi anemia (PMIDs: 28717661 (2017), 24584348 (2014), 22778927 (2012), 21273304 (2011), 21659346 (2011), 19367192 (2009), 17924555 (2008), 10094191 (1999), 9371798 (1997)), and in individuals with hereditary breast cancer (PMID: 32235514 (2020)). This variant is thought to be the most common FANCA mutation in the world, and is present in many different ethnicities, especially Hispanic and Caucasian populations (PMID: 9371798 (1997)). In functional studies, this variant was shown to have a damaging effect on FANCA protein function and cellular interaction (PMIDs: 21273304 (2011), 12444097 (2002)). Based on the available information, this variant is classified as pathogenic. -

Jan 17, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: Impaired FANCA phosphorylation, FANCD2 monoubiquitination, nuclear localization, and interaction with FANCC and FANCF (PMID: 12444097); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15643609, 21659346, 9371798, 24584348, 26740942, 21273304, 26556299, 29904161, 31030435, 28717661, 32235514, 31019026, 31980526, 31558676, 33960719, 33679882, 31589614, 33172906, 32793304, 33718801, 35295078, 34308104, 34958143, 30809872, 35988656, 36113475, 34645491, 36135330, 12444097) -

FANCA-related disorder Pathogenic:1
Feb 07, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The FANCA c.3788_3790delTCT variant is predicted to result in an in-frame deletion (p.Phe1263del). This variant has been reported in the homozygous or compound heterozygous state in many individuals with Fanconi anemia (Levran et al 1997. PubMed ID: 9371798; Castella et al 2011. PubMed ID: 21273304; Steinberg-Shemer et al. 2020. PubMed ID: 31558676; Thompson et al. 2021. PubMed ID: 33960719). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD, and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/41003/). This variant is interpreted as pathogenic. -

not specified Other:1
Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397507553; hg19: chr16-89807249; API