rs458017

Positions:

• chr6-111374888-T-C

Variant summary

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

The ENST00000368802.8(REV3L):​c.3467A>G​(p.Tyr1156Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0613 in 1,613,740 control chromosomes in the GnomAD database, including 3,293 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 0.056 (271 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3022 hom.)
• Consequence: REV3L ENST00000368802.8 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.168

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:21053): (major facilitator superfamily domain containing 4B) Predicted to enable glucose transmembrane transporter activity. Predicted to be involved in glucose transmembrane transport and sodium ion transport. Predicted to be located in apical plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.0019741356).
• BP6: Variant 6-111374888-T-C is Benign according to our data. Variant chr6-111374888-T-C is described in ClinVar as [Benign]. Clinvar id is 3037951.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REV3L	NM_001372078.1	c.3467A>G	p.Tyr1156Cys	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.3467A>G	p.Tyr1156Cys	missense_variant	13/32	1	NM_001372078.1	ENSP00000357792	P4

Frequencies

GnomAD3 genomes AF: 0.0561 AC: 8537 AN: 152140 Hom.: 272 Cov.: 32

Gnomad AFR AF: 0.0443

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.0476

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.0445

Gnomad FIN AF: 0.0619

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0633

Gnomad OTH AF: 0.0726

GnomAD3 exomes AF: 0.0593 AC: 14855 AN: 250414 Hom.: 518 AF XY: 0.0598 AC XY: 8097 AN XY: 135480

Gnomad AFR exome AF: 0.0452

Gnomad AMR exome AF: 0.0613

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0500

Gnomad FIN exome AF: 0.0671

Gnomad NFE exome AF: 0.0631

Gnomad OTH exome AF: 0.0666

GnomAD4 exome AF: 0.0618 AC: 90370 AN: 1461482 Hom.: 3022 Cov.: 45 AF XY: 0.0619 AC XY: 44974 AN XY: 727018

Gnomad4 AFR exome AF: 0.0437

Gnomad4 AMR exome AF: 0.0612

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0530

Gnomad4 FIN exome AF: 0.0667

Gnomad4 NFE exome AF: 0.0628

Gnomad4 OTH exome AF: 0.0651

GnomAD4 genome AF: 0.0561 AC: 8539 AN: 152258 Hom.: 271 Cov.: 32 AF XY: 0.0542 AC XY: 4038 AN XY: 74452

Gnomad4 AFR AF: 0.0442

Gnomad4 AMR AF: 0.0476

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.0446

Gnomad4 FIN AF: 0.0619

Gnomad4 NFE AF: 0.0634

Gnomad4 OTH AF: 0.0718

Alfa AF: 0.0649 Hom.: 879

Bravo AF: 0.0562

TwinsUK AF: 0.0653 AC: 242

ALSPAC AF: 0.0615 AC: 237

ESP6500AA AF: 0.0477 AC: 210

ESP6500EA AF: 0.0673 AC: 579

ExAC AF: 0.0570 AC: 6924

Asia WGS AF: 0.0250 AC: 88 AN: 3478

EpiCase AF: 0.0674

EpiControl AF: 0.0640

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

Mar 01, 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	0.060
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.3
DANN	Benign	0.37
DEOGEN2	Benign	0.12	T;T;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.41	.;.;T;T
MetaRNN	Benign	0.0020	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.82	N;N;N;N
REVEL	Benign	0.020
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.0020	B;B;.;B
Vest4		0.092
MPC		0.077
ClinPred		0.00060	T
GERP RS		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.049
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs458017; hg19: chr6-111696091; COSMIC: COSV62619020;