rs786204204

Positions:

• chr16-89814517-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_000135.4(FANCA):​c.283+3A>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FANCA NM_000135.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9211
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -1.09

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-89814517-T-G is Pathogenic according to our data. Variant chr16-89814517-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 188302.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-89814517-T-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCA	NM_000135.4	c.283+3A>C		splice_donor_region_variant, intron_variant		ENST00000389301.8	NP_000126.2
FANCA	NM_001018112.3	c.283+3A>C		splice_donor_region_variant, intron_variant			NP_001018122.1
FANCA	NM_001286167.3	c.283+3A>C		splice_donor_region_variant, intron_variant			NP_001273096.1
FANCA	NM_001351830.2	c.283+3A>C		splice_donor_region_variant, intron_variant			NP_001338759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.283+3A>C		splice_donor_region_variant, intron_variant		1	NM_000135.4	ENSP00000373952	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 15, 2023

For these reasons, this variant has been classified as Pathogenic. 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 skipping of exon 3 and introduces a premature termination codon (PMID: 12955722). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 188302). This variant has been observed in individual(s) with fanconi anemia (PMID: 12955722). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 3 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 may result in an absent or disrupted protein product. -

Fanconi anemia complementation group A Pathogenic:1

Pathogenic, no assertion criteria provided

curation

Leiden Open Variation Database

Feb 28, 2020

Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.7
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Benign	0.58
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.81		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204204; hg19: chr16-89880925;