2-99403025-G-C

Variant names:

• chr2-99403025-G-C
• rs1027984374
• NM_016316.4:c.3248C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016316.4(REV1):​c.3248C>G​(p.Pro1083Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P1083L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: REV1 NM_016316.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.237
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057257652).

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.3248C>G	p.Pro1083Arg	missense	Exon 20 of 23	NP_057400.1	Q9UBZ9-1
	REV1	NM_001321454.2		c.3356C>G	p.Pro1119Arg	missense	Exon 21 of 24	NP_001308383.1
	REV1	NM_001037872.3		c.3245C>G	p.Pro1082Arg	missense	Exon 20 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.3248C>G	p.Pro1083Arg	missense	Exon 20 of 23	ENSP00000258428.3	Q9UBZ9-1
	REV1	ENST00000393445.7	TSL:1	c.3245C>G	p.Pro1082Arg	missense	Exon 20 of 23	ENSP00000377091.3	Q9UBZ9-2
	REV1	ENST00000879664.1		c.3356C>G	p.Pro1119Arg	missense	Exon 21 of 24	ENSP00000549723.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251196 AF XY: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1461776 Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23 AN XY: 727210

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.3
DANN	Benign	0.74
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.24
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.051
Sift	Benign	0.24	T
Sift4G	Benign	0.16	T
Polyphen		0.026	B
Vest4		0.13
MutPred		0.31		Gain of solvent accessibility (P = 0.0055)
MVP		0.21
MPC		0.12
ClinPred		0.081	T
GERP RS		-11
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.054
gMVP		0.21
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1027984374; hg19: chr2-100019488;