rs794726660

Positions:

• chr16-89742840-ATGTTT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000135.4(FANCA):​c.3720_3724delAAACA​(p.Glu1240fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FANCA NM_000135.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -0.261

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-89742840-ATGTTT-A is Pathogenic according to our data. Variant chr16-89742840-ATGTTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 3448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89742840-ATGTTT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCA	NM_000135.4	c.3720_3724delAAACA	p.Glu1240fs	frameshift_variant	37/43	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3	c.3720_3724delAAACA	p.Glu1240fs	frameshift_variant	37/43		NP_001273096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.3720_3724delAAACA	p.Glu1240fs	frameshift_variant	37/43	1	NM_000135.4	ENSP00000373952.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461864 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group A Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 07, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2004	- -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Myungshin Kim. -

Fanconi anemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 10, 2023	This sequence change creates a premature translational stop signal (p.Glu1240Aspfs*36) in the FANCA gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Fanconi anemia (PMID: 15523645, 23067021). ClinVar contains an entry for this variant (Variation ID: 3448). Studies have shown that this premature translational stop signal results in skipping of exon 37 and introduces a premature termination codon (PMID: 15523645). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 16, 2024	Variant summary: FANCA c.3720_3724delAAACA (p.Glu1240AspfsX36) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251474 control chromosomes (gnomAD). c.3720_3724delAAACA has been reported in the literature in individuals affected with Fanconi Anemia (e.g. Mori_2019). The following publication has been ascertained in the context of this evaluation (PMID: 30792206). ClinVar contains an entry for this variant (Variation ID: 3448). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs794726660; hg19: chr16-89809248;