rs757468756

Positions:

• chr16-89816593-T-A
• chr16-89816593-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000389301.8(FANCA):​c.23A>T​(p.Asn8Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,374,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N8S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: FANCA ENST00000389301.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.84

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2670835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCA	NM_000135.4	c.23A>T	p.Asn8Ile	missense_variant	1/43	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3	c.23A>T	p.Asn8Ile	missense_variant	1/43		NP_001273096.1
FANCA	NM_001018112.3	c.23A>T	p.Asn8Ile	missense_variant	1/11		NP_001018122.1
FANCA	NM_001351830.2	c.23A>T	p.Asn8Ile	missense_variant	1/10		NP_001338759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.23A>T	p.Asn8Ile	missense_variant	1/43	1	NM_000135.4	ENSP00000373952	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1374818 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 679430

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2021

This sequence change replaces asparagine with isoleucine at codon 8 of the FANCA protein (p.Asn8Ile). The asparagine residue is weakly conserved and there is a large physicochemical difference between asparagine and isoleucine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with FANCA-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.0050
DANN	Benign	0.77
DEOGEN2	Benign	0.062	T;.;.;T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.59	T;T;T;T;T;T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.27	T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.0	N;N;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.35	N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.017	D;D;D;D;D;D
Sift4G	Benign	0.10	T;T;D;D;D;D
Polyphen		0.018	B;.;.;.;B;B
Vest4		0.23
MutPred		0.26		Loss of solvent accessibility (P = 0.0058);Loss of solvent accessibility (P = 0.0058);Loss of solvent accessibility (P = 0.0058);Loss of solvent accessibility (P = 0.0058);Loss of solvent accessibility (P = 0.0058);Loss of solvent accessibility (P = 0.0058);
MVP		0.59
ClinPred		0.19	T
GERP RS		-8.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.098
gMVP		0.10

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

Other links and lift over

dbSNP: rs757468756; hg19: chr16-89883001;