rs462779

Positions:

• chr6-111374684-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BA1

The NM_001372078.1(REV3L):​c.3671C>T​(p.Thr1224Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.769 in 1,612,660 control chromosomes in the GnomAD database, including 486,868 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.67 (36564 hom., cov: 31)
  • Exomes 𝑓: 0.78 (450304 hom.)
• Consequence: REV3L NM_001372078.1 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.438

Genes affected

REV3L (HGNC:9968): (REV3 like, DNA directed polymerase zeta catalytic subunit) The protein encoded by this gene represents the catalytic subunit of DNA polymerase zeta, which functions in translesion DNA synthesis. The encoded protein can be found in mitochondria, where it protects DNA from damage. Defects in this gene are a cause of Mobius syndrome. [provided by RefSeq, Jan 2017]

MFSD4B (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), REV3L. . Gene score misZ 2.4677 (greater than the threshold 3.09). Trascript score misZ 3.98 (greater than threshold 3.09). GenCC has associacion of gene with Mobius syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=9.095963E-7).
• BP6: Variant 6-111374684-G-A is Benign according to our data. Variant chr6-111374684-G-A is described in ClinVar as [Benign]. Clinvar id is 3059806.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REV3L	NM_001372078.1	c.3671C>T	p.Thr1224Ile	missense_variant	13/32	ENST00000368802.8	NP_001359007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REV3L	ENST00000368802.8	c.3671C>T	p.Thr1224Ile	missense_variant	13/32	1	NM_001372078.1	ENSP00000357792.3

Frequencies

GnomAD3 genomes AF: 0.673 AC: 102206 AN: 151876 Hom.: 36556 Cov.: 31

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.738

Gnomad AMR AF: 0.710

Gnomad ASJ AF: 0.786

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.717

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.813

Gnomad OTH AF: 0.713

GnomAD3 exomes AF: 0.718 AC: 179543 AN: 250086 Hom.: 66509 AF XY: 0.730 AC XY: 98834 AN XY: 135398

Gnomad AFR exome AF: 0.422

Gnomad AMR exome AF: 0.677

Gnomad ASJ exome AF: 0.784

Gnomad EAS exome AF: 0.458

Gnomad SAS exome AF: 0.716

Gnomad FIN exome AF: 0.704

Gnomad NFE exome AF: 0.809

Gnomad OTH exome AF: 0.763

GnomAD4 exome AF: 0.779 AC: 1137992 AN: 1460666 Hom.: 450304 Cov.: 52 AF XY: 0.779 AC XY: 566158 AN XY: 726634

Gnomad4 AFR exome AF: 0.407

Gnomad4 AMR exome AF: 0.687

Gnomad4 ASJ exome AF: 0.788

Gnomad4 EAS exome AF: 0.403

Gnomad4 SAS exome AF: 0.721

Gnomad4 FIN exome AF: 0.710

Gnomad4 NFE exome AF: 0.816

Gnomad4 OTH exome AF: 0.757

GnomAD4 genome AF: 0.673 AC: 102260 AN: 151994 Hom.: 36564 Cov.: 31 AF XY: 0.668 AC XY: 49639 AN XY: 74288

Gnomad4 AFR AF: 0.434

Gnomad4 AMR AF: 0.710

Gnomad4 ASJ AF: 0.786

Gnomad4 EAS AF: 0.445

Gnomad4 SAS AF: 0.717

Gnomad4 FIN AF: 0.694

Gnomad4 NFE AF: 0.813

Gnomad4 OTH AF: 0.709

Alfa AF: 0.789 Hom.: 117099

Bravo AF: 0.662

TwinsUK AF: 0.816 AC: 3025

ALSPAC AF: 0.818 AC: 3151

ESP6500AA AF: 0.440 AC: 1939

ESP6500EA AF: 0.813 AC: 6990

ExAC AF: 0.715 AC: 86818

Asia WGS AF: 0.590 AC: 2053 AN: 3478

EpiCase AF: 0.820

EpiControl AF: 0.820

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

REV3L-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.65
DANN	Benign	0.10
DEOGEN2	Benign	0.050	T;T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.11	.;.;T;T
MetaRNN	Benign	9.1e-7	T;T;T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.82	N;N;N;N
REVEL	Benign	0.050
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.050
MPC		0.066
ClinPred		0.0063	T
GERP RS		1.4
Varity_R		0.018
gMVP		0.092

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: rs462779; hg19: chr6-111695887; COSMIC: COSV62622779;