2-99405980-T-C

Position:

• chr2-99405980-T-C

Variant summary

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

The NM_016316.4(REV1):​c.2741A>G​(p.Asn914Ser) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: REV1 NM_016316.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80

Genes affected

REV1 (HGNC:14060): (REV1 DNA directed polymerase) This gene encodes a protein with similarity to the S. cerevisiae mutagenesis protein Rev1. The Rev1 proteins contain a BRCT domain, which is important in protein-protein interactions. A suggested role for the human Rev1-like protein is as a scaffold that recruits DNA polymerases involved in translesion synthesis (TLS) of damaged DNA. [provided by RefSeq, Mar 2016]

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=0.28777552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REV1	NM_016316.4	c.2741A>G	p.Asn914Ser	missense_variant	17/23	ENST00000258428.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REV1	ENST00000258428.8	c.2741A>G	p.Asn914Ser	missense_variant	17/23	1	NM_016316.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2023

The c.2741A>G (p.N914S) alteration is located in exon 17 (coding exon 16) of the REV1 gene. This alteration results from a A to G substitution at nucleotide position 2741, causing the asparagine (N) at amino acid position 914 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.8	.;M
MutationTaster	Benign	0.85	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.11
Sift	Benign	0.067	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.91	P;D
Vest4		0.41
MutPred		0.18		.;Gain of phosphorylation at N914 (P = 0.0951);
MVP		0.58
MPC		0.30
ClinPred		0.91	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.21

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: rs1224725170; hg19: chr2-100022442;