16-89783098-T-C

Position:

• chr16-89783098-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_000135.4(FANCA):​c.1475A>G​(p.His492Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H492L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 6.31

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-89783098-T-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 16-89783098-T-C is Pathogenic according to our data. Variant chr16-89783098-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 553955.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr16-89783098-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCA	NM_000135.4	c.1475A>G	p.His492Arg	missense_variant	16/43	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3	c.1475A>G	p.His492Arg	missense_variant	16/43		NP_001273096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.1475A>G	p.His492Arg	missense_variant	16/43	1	NM_000135.4	ENSP00000373952.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi anemia complementation group A Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 16, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 20, 2017	- -
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
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.88		Loss of phosphorylation at Y488 (P = 0.2291);Loss of phosphorylation at Y488 (P = 0.2291);
MVP		1.0
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs925457555; hg19: chr16-89849506;