rs149797103

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP5BP4BP7

The NM_000135.4(FANCA):c.3624C>T(p.Ser1208=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,611,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

FANCA
NM_000135.4 splice_region, synonymous

Scores

Splicing: ADA: 0.09924

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: -0.241

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-89744961-G-A is Pathogenic according to our data. Variant chr16-89744961-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 419528.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Uncertain_significance=1, Pathogenic=1}. Variant chr16-89744961-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).. Strength limited to SUPPORTING due to the PP5.

BP7

Synonymous conserved (PhyloP=-0.241 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4 linkuse as main transcript	c.3624C>T	p.Ser1208=	splice_region_variant, synonymous_variant	36/43	ENST00000389301.8
FANCA	NM_001286167.3 linkuse as main transcript	c.3624C>T	p.Ser1208=	splice_region_variant, synonymous_variant	36/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8 linkuse as main transcript	c.3624C>T	p.Ser1208=	splice_region_variant, synonymous_variant	36/43	1	NM_000135.4	P1	O15360-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152210

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:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000969

AC:

AN:

247702

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

134316

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.000450

Gnomad NFE exome

AF:

0.000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000576

AC:

AN:

1459240

Hom.:

Cov.:

AF XY:

0.0000496

AC XY:

AN XY:

726014

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000761

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.0000227

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 03, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	May 31, 2023	The FANCA c.3624C>T (p.Ser1208=) synonymous change has a maximum founder subpopulation frequency of 0.055% and a maximum non-founder subpopulation frequency of 0.011% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Algorithms that predict the impact of sequence changes on splicing indicate that this change may activate a cryptic donor splice site. This variant has been reported in several individuals with Fanconi anemia (PMID: 17924555, 22778927, 28104920, 29098742, 35417938). In summary, this variant meets criteria to be classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 11, 2016	- -

Fanconi anemia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2023	Variant summary: FANCA c.3624C>T (p.Ser1208Ser) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. The TraP (transcript-inferred pathogenicity) in silico prediction tool scores the variant as possibly pathogenic. At least one publication reports experimental evidence that this variant causes aberrant mRNA splicing (Ameziane_2008). The variant allele was found at a frequency of 9.7e-05 in 247702 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FANCA causing Fanconi Anemia (9.7e-05 vs 0.0022), allowing no conclusion about variant significance. c.3624C>T has been reported in the literature in multiple individuals affected with Fanconi Anemia (e.g., Chandra_2005, Ameziane_2008, Gille_2012, Guidugli_2017, Kimble_2018). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) have cited the variant, classifying it as likely pathogenic (n = 3) or uncertain significance (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 16, 2022	This sequence change affects codon 1208 of the FANCA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FANCA protein. This variant is present in population databases (rs149797103, gnomAD 0.07%). This variant has been observed in individuals with clinical features of Fanconi anemia (PMID: 17924555, 22778927, 29098742). ClinVar contains an entry for this variant (Variation ID: 419528). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2021	In silico analysis supports a deleterious effect on splicing (predicts destruction of the natural splice donor site and creation of a cryptic splice donor site in exon 36); This variant is associated with the following publications: (PMID: 29098742, 31618753, 17924555, no PMID, 16084127, 22778927, 25525159) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -

FANCA-related condition

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2023

The FANCA c.3624C>T variant is not predicted to result in an amino acid change (p.=). This variant was reported along with a second protein-truncating variant (nonsense, frameshift, start loss, and large exonic deletions) in at least six unrelated individuals with Fanconi anemia (Ameziane et al. 2008. PubMed ID: 17924555; Gille et al. 2012. PubMed ID: 22778927; Guidugli et al. 2017. PubMed ID: 28104920; Kimble et al. 2018. PubMed ID: 29098742; Table S5, Altintas et al. 2023. PubMed ID: 35417938). This variant is predicted to alter splicing based on available splicing prediction programs (Alamut Visual Plus v1.6.1) and this variant has been described to result in splicing errors on cDNA (Table 1, Ameziane et al. 2008. PubMed ID: 17924555). This variant is reported in 0.055% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-89811369-G-A) and is interpreted as pathogenic or likely pathogenic by most submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/419528/). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

Cadd

Benign

Dann

Benign

0.83

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.099

dbscSNV1_RF

Benign

0.65

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.98

Position offset: 2

DS_DL_spliceai

0.30

Position offset: -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