rs1555545583

Positions:

• chr16-89765061-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000135.4(FANCA):​c.2607G>C​(p.Gln869His) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q869P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000135.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-89765062-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 215981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.2607G>C	p.Gln869His	missense_variant	28/43	ENST00000389301.8
FANCA	NM_001286167.3	c.2607G>C	p.Gln869His	missense_variant	28/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.2607G>C	p.Gln869His	missense_variant	28/43	1	NM_000135.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Apr 03, 2017

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. A different missense substitution at this codon (p.Gln869Pro) has been reported in individuals affected with Fanconi anemia in the literature (PMID: 15643609) and in the Leiden Open-source Variation Database (PMID: 21520333), however, in some of these individuals, a second FANCA variant was not identified. In addition, an experimental study demonstrates that this variant may disrupt FANCA protein complex formation with FANCB and FANCL (PMID: 16720839). This suggests that the glutamine residue is may be critical for FANCA protein function. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FANCA-related disease. This sequence change replaces glutamine with histidine at codon 869 of the FANCA protein (p.Gln869His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.91	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.37		Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);
MVP		0.95
ClinPred		0.94	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.41		Position offset: -15
DS_AL_spliceai		0.30		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555545583; hg19: chr16-89831469;