chr2-99403701-C-G

Variant names:

• chr2-99403701-C-G
• rs533170369
• NM_016316.4:c.3160G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016316.4(REV1):​c.3160G>C​(p.Ala1054Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A1054T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: REV1 NM_016316.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08056414).

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.3160G>C	p.Ala1054Pro	missense	Exon 19 of 23	NP_057400.1	Q9UBZ9-1
	REV1	NM_001321454.2		c.3268G>C	p.Ala1090Pro	missense	Exon 20 of 24	NP_001308383.1
	REV1	NM_001037872.3		c.3157G>C	p.Ala1053Pro	missense	Exon 19 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.3160G>C	p.Ala1054Pro	missense	Exon 19 of 23	ENSP00000258428.3	Q9UBZ9-1
	REV1	ENST00000393445.7	TSL:1	c.3157G>C	p.Ala1053Pro	missense	Exon 19 of 23	ENSP00000377091.3	Q9UBZ9-2
	REV1	ENST00000879664.1		c.3268G>C	p.Ala1090Pro	missense	Exon 20 of 24	ENSP00000549723.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

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: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.035
DANN	Benign	0.75
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-1.2
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.059
Sift	Benign	0.27	T
Sift4G	Benign	0.27	T
Polyphen		0.91	P
Vest4		0.15
MutPred		0.21		Gain of glycosylation at A1054 (P = 0.0307)
MVP		0.37
MPC		0.23
ClinPred		0.20	T
GERP RS		-12
Varity_R		0.077
gMVP		0.31
Mutation Taster		=94/6	polymorphism

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: rs533170369; hg19: chr2-100020164;