16-89805275-C-T

Position:

chr16-89805275-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000135.4(FANCA):c.709+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000932 in 1,608,624 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 1 hom. )

Consequence

FANCA
NM_000135.4 splice_donor_5th_base, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 3.45

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 16-89805275-C-T is Pathogenic according to our data. Variant chr16-89805275-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 408169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89805275-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
FANCA	NM_000135.4 linkuse as main transcript	c.709+5G>A	splice_donor_5th_base_variant, intron_variant	ENST00000389301.8
FANCA	NM_001018112.3 linkuse as main transcript	c.709+5G>A	splice_donor_5th_base_variant, intron_variant
FANCA	NM_001286167.3 linkuse as main transcript	c.709+5G>A	splice_donor_5th_base_variant, intron_variant
FANCA	NM_001351830.2 linkuse as main transcript	c.613+5G>A	splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8 linkuse as main transcript	c.709+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_000135.4	P1	O15360-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248220

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134388

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000961

AC:

AN:

1456492

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

724752

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000813

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000361

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000877

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 01, 2020	The FANCA:c.709+5G>A variant is a single base change located in intron 7. The variant has been reported in the literature in individuals with a second pathogenic FANCA variant and is associated with disease (PMID: 21273304, PMID: 29098742) (PS1). RNA studies demonstrate that the variant results in aberrant splicing and the insertion of 30bp intronic sequence. The insertion adds 10 amino acids in-frame between codons 236 and 237 (PMID: 8896563). Functional studies show that the variant is unable to restore FANCD2 monoubiquitination in FANCA-deficient lymphoblasts supporting its pathogenicity (PMID: 19423727) (PS3). The variant is rare in population databases at 0.002% (5 het/ 279588 allele count) (PP). It is described in ClinVar as pathogenic/ likely pathogenic and HGMD (2020.1) as disease causing (PP5). Splice prediction programs in Alamut also predict the variant will remove the exon 7 donor site. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 06, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 07, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 02, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2024	- -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter, Johan den Dunnen. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 14, 2021	DNA sequence analysis of the FANCA gene demonstrated a sequence change located near the canonical splice donor site in intron 7, c.709+5G>A. This sequence change has been described in the gnomAD database with a frequency of 0.02% in the East Asian subpopulation (dbSNP rs759877008). This sequence change has been previously described, along with other pathogenic variants, in the individuals with Fanconi anemia (PMID: 21273304, 8896563, 19423727, 10094191) and in the heterozygous state in an individual with a personal history of ovarian cancer and family history of Lynch syndrome related cancers (PMID: 32235514). Based on in-silico splice prediction programs, this sequence change likely affects normal splicing of the FANCA gene and an experimental study demonstrated that this sequence change impacts normal splicing leading to the production of an abnormal protein with impaired function (PMID: 19423727). Based on these collective evidences, this sequence change is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 24, 2022	The frequency of this variant in the general population, 0.0002 (4/19948 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been detected in individuals with Fanconi Anemia. Those individuals were compound heterozygous for the variant and a pathogenic variant in the FANCA gene (PMID: 17924555 (2008), 19423727 (2009), 21273304 (2011), 29098742 (2018)) . It has been reported in an individual with ovarian cancer (PMID: 32235514 (2020)). A functional study has demonstrated that this variant has a deleterious effect on FANCA protein function (PMID: 19423727 (2009)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper FANCA mRNA splicing . Based on the available information, this variant is classified as pathogenic. -

Fanconi anemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2023

This sequence change falls in intron 7 of the FANCA gene. It does not directly change the encoded amino acid sequence of the FANCA protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 10 novel amino acids amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs759877008, gnomAD 0.02%). This variant has been observed in individual(s) with Fanconi anemia (PMID: 8896563, 10094191, 19423727, 21273304). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 740+5G>A or IVS7+5G>A. ClinVar contains an entry for this variant (Variation ID: 408169). 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: 19423727). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in intron 7 (PMID: 19423727). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

SpliceAI score (max)

0.74

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.74

Position offset: 5

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