rs397507553

Positions:

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]

FANCA links:

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]

ZNF276 links:

FANCA (HGNC:):

FANCA links:

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/exons	MANE	Protein	UniProt
FANCA	NM_000135.4 linkuse as main transcript	c.3788_3790delTCT	p.Phe1263del	disruptive_inframe_deletion	38/43	ENST00000389301.8	NP_000126.2	O15360-1
ZNF276	NM_001113525.2 linkuse as main transcript	c.2603_2605delGAA		3_prime_UTR_variant	11/11	ENST00000443381.7	NP_001106997.1	Q8N554-1I6L9I3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 linkuse as main transcript	c.3788_3790delTCT	p.Phe1263del	disruptive_inframe_deletion	38/43	1	NM_000135.4	ENSP00000373952.3		O15360-1
ZNF276	ENST00000443381.7 linkuse as main transcript	c.2603_2605delGAA		3_prime_UTR_variant	11/11	1	NM_001113525.2	ENSP00000415836.2		Q8N554-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152092

Hom.:

Cov.:

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:

AN:

250632

Hom.:

AF XY:

0.000118

AC XY:

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.:

AF XY:

0.000105

AC XY:

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:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

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.:

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

Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Daniela Pilonetto, Johan de Winter, Sue Richards. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 31, 2023	ACMG classification criteria: PS3 supporting, PM2 supporting, PM3 very strong, PM4 -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 24, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 16, 2022	- -
Pathogenic, criteria provided, single submitter	research	Human Genetics Section, Sidra Medicine	Jul 11, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 11, 2022	- -

Fanconi anemia

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Dec 08, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Feb 01, 2018	- -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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. ClinVar contains an entry for this variant (Variation ID: 41003). Algorithms developed to predict the effect of variants on protein 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. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 03, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	FANCA: PM3:Strong, PM2, PM4, PS3:Moderate -

FANCA-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2024

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

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over