chr2-99439044-A-G

Variant names:

• chr2-99439044-A-G
• rs3087386
• NM_016316.4:c.770T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 60 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016316.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REV1	NM_016316.4	MANE Select	c.770T>C	p.Phe257Ser	missense	Exon 6 of 23	NP_057400.1
	REV1	NM_001321454.2		c.770T>C	p.Phe257Ser	missense	Exon 6 of 24	NP_001308383.1
	REV1	NM_001037872.3		c.770T>C	p.Phe257Ser	missense	Exon 6 of 23	NP_001032961.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REV1	ENST00000258428.8	TSL:1 MANE Select	c.770T>C	p.Phe257Ser	missense	Exon 6 of 23	ENSP00000258428.3
	REV1	ENST00000393445.7	TSL:1	c.770T>C	p.Phe257Ser	missense	Exon 6 of 23	ENSP00000377091.3
	REV1	ENST00000413697.5	TSL:2	n.*717T>C		non_coding_transcript_exon	Exon 7 of 23	ENSP00000416274.1

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

GnomAD2 exomes AF: 0.578 AC: 144782 AN: 250650 AF XY: 0.565

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 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

African (AFR) AF: 0.713 AC: 23863 AN: 33478

American (AMR) AF: 0.720 AC: 32206 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 12628 AN: 26132

East Asian (EAS) AF: 0.345 AC: 13696 AN: 39696

South Asian (SAS) AF: 0.506 AC: 43668 AN: 86252

European-Finnish (FIN) AF: 0.647 AC: 34559 AN: 53392

Middle Eastern (MID) AF: 0.466 AC: 2688 AN: 5764

European-Non Finnish (NFE) AF: 0.556 AC: 618215 AN: 1111728

Other (OTH) AF: 0.547 AC: 33033 AN: 60384

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

African (AFR) AF: 0.712 AC: 29513 AN: 41440

American (AMR) AF: 0.657 AC: 10050 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1736 AN: 3470

East Asian (EAS) AF: 0.361 AC: 1864 AN: 5168

South Asian (SAS) AF: 0.515 AC: 2477 AN: 4812

European-Finnish (FIN) AF: 0.671 AC: 7084 AN: 10564

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.554 AC: 37671 AN: 67948

Other (OTH) AF: 0.564 AC: 1192 AN: 2112

Alfa AF: 0.566 Hom.: 78374

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 v4.9

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
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.0	N
PhyloP100		0.90
PrimateAI	Benign	0.23	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.029
Sift	Benign	0.47	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.054
MPC		0.19
ClinPred		0.012	T
GERP RS		-0.027
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.20
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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