rs3087386

Positions:

• chr2-99439044-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016316.4(REV1):​c.770T>C​(p.Phe257Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,613,544 control chromosomes in the GnomAD database, including 258,604 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.61 (28676 hom., cov: 32)
  • Exomes 𝑓: 0.56 (229928 hom.)
• Consequence: REV1 NM_016316.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.902

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0208001E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REV1	NM_016316.4	c.770T>C	p.Phe257Ser	missense_variant	6/23	ENST00000258428.8	NP_057400.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REV1	ENST00000258428.8	c.770T>C	p.Phe257Ser	missense_variant	6/23	1	NM_016316.4	ENSP00000258428.3

Frequencies

GnomAD3 genomes AF: 0.607 AC: 92186 AN: 151900 Hom.: 28640 Cov.: 32

Gnomad AFR AF: 0.712

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.656

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.515

Gnomad FIN AF: 0.671

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.554

Gnomad OTH AF: 0.567

GnomAD3 exomes AF: 0.578 AC: 144782 AN: 250650 Hom.: 43058 AF XY: 0.565 AC XY: 76554 AN XY: 135412

Gnomad AFR exome AF: 0.717

Gnomad AMR exome AF: 0.731

Gnomad ASJ exome AF: 0.480

Gnomad EAS exome AF: 0.358

Gnomad SAS exome AF: 0.508

Gnomad FIN exome AF: 0.655

Gnomad NFE exome AF: 0.560

Gnomad OTH exome AF: 0.561

GnomAD4 exome AF: 0.557 AC: 814556 AN: 1461526 Hom.: 229928 Cov.: 55 AF XY: 0.554 AC XY: 402687 AN XY: 727038

Gnomad4 AFR exome AF: 0.713

Gnomad4 AMR exome AF: 0.720

Gnomad4 ASJ exome AF: 0.483

Gnomad4 EAS exome AF: 0.345

Gnomad4 SAS exome AF: 0.506

Gnomad4 FIN exome AF: 0.647

Gnomad4 NFE exome AF: 0.556

Gnomad4 OTH exome AF: 0.547

GnomAD4 genome AF: 0.607 AC: 92271 AN: 152018 Hom.: 28676 Cov.: 32 AF XY: 0.610 AC XY: 45304 AN XY: 74316

Gnomad4 AFR AF: 0.712

Gnomad4 AMR AF: 0.657

Gnomad4 ASJ AF: 0.500

Gnomad4 EAS AF: 0.361

Gnomad4 SAS AF: 0.515

Gnomad4 FIN AF: 0.671

Gnomad4 NFE AF: 0.554

Gnomad4 OTH AF: 0.564

Alfa AF: 0.555 Hom.: 47988

Bravo AF: 0.614

TwinsUK AF: 0.560 AC: 2078

ALSPAC AF: 0.544 AC: 2096

ESP6500AA AF: 0.707 AC: 3115

ESP6500EA AF: 0.547 AC: 4708

ExAC AF: 0.574 AC: 69739

Asia WGS AF: 0.479 AC: 1663 AN: 3478

EpiCase AF: 0.546

EpiControl AF: 0.561

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.47
DANN	Benign	0.48
DEOGEN2	Benign	0.010	.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.033	T;T
MetaRNN	Benign	0.0000010	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	1.4	N;N
REVEL	Benign	0.029
Sift	Benign	0.47	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.0	B;B
Vest4		0.054
MPC		0.19
ClinPred		0.012	T
GERP RS		-0.027
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.20

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: rs3087386; hg19: chr2-100055506; COSMIC: COSV51482947; COSMIC: COSV51482947;