2-99402317-C-T

Variant names:

• chr2-99402317-C-T
• rs1455918852
• NM_016316.4:c.3571G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016316.4(REV1):​c.3571G>A​(p.Val1191Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000429 in 1,539,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: REV1 NM_016316.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.53
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REV1	NM_016316.4	MANE Select	c.3571G>A	p.Val1191Met	missense	Exon 22 of 23	NP_057400.1	Q9UBZ9-1
	REV1	NM_001321454.2		c.3679G>A	p.Val1227Met	missense	Exon 23 of 24	NP_001308383.1
	REV1	NM_001037872.3		c.3568G>A	p.Val1190Met	missense	Exon 22 of 23	NP_001032961.1	Q9UBZ9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REV1	ENST00000258428.8	TSL:1 MANE Select	c.3571G>A	p.Val1191Met	missense	Exon 22 of 23	ENSP00000258428.3	Q9UBZ9-1
	REV1	ENST00000393445.7	TSL:1	c.3568G>A	p.Val1190Met	missense	Exon 22 of 23	ENSP00000377091.3	Q9UBZ9-2
	REV1	ENST00000879664.1		c.3679G>A	p.Val1227Met	missense	Exon 23 of 24	ENSP00000549723.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000933 AC: 2 AN: 214334 AF XY: 0.00000871

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000212

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000469 AC: 65 AN: 1387084 Hom.: 0 Cov.: 24 AF XY: 0.0000550 AC XY: 38 AN XY: 690772

African (AFR) AF: 0.00 AC: 0 AN: 31736

American (AMR) AF: 0.00 AC: 0 AN: 40094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39282

South Asian (SAS) AF: 0.00 AC: 0 AN: 80094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 0.0000606 AC: 64 AN: 1055346

Other (OTH) AF: 0.0000173 AC: 1 AN: 57696

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74310

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000282 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.26
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.38		Loss of methylation at K1192 (P = 0.0306)
MVP		0.55
MPC		2.6
ClinPred		0.79	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.60
Mutation Taster		=50/50

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: rs1455918852; hg19: chr2-100018780;