6-111372921-C-G

Position:

• chr6-111372921-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_001372078.1(REV3L):​c.5434G>C​(p.Asp1812His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,614,002 control chromosomes in the GnomAD database, including 342 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.014 (22 hom., cov: 32)
  • Exomes 𝑓: 0.019 (320 hom.)
• Consequence: REV3L NM_001372078.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.43

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 -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, REV3L
• BP4: Computational evidence support a benign effect (MetaRNN=0.007606685).
• BP6: Variant 6-111372921-C-G is Benign according to our data. Variant chr6-111372921-C-G is described in ClinVar as [Benign]. Clinvar id is 3041876.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0139 (2111/152246) while in subpopulation NFE AF= 0.02 (1359/68012). AF 95% confidence interval is 0.0191. There are 22 homozygotes in gnomad4. There are 1036 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2111 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REV3L	NM_001372078.1	c.5434G>C	p.Asp1812His	missense_variant	13/32	ENST00000368802.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REV3L	ENST00000368802.8	c.5434G>C	p.Asp1812His	missense_variant	13/32	1	NM_001372078.1	P4

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2111 AN: 152128 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0200

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.0142 AC: 3561 AN: 251326 Hom.: 38 AF XY: 0.0140 AC XY: 1896 AN XY: 135828

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.0144

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.0213

Gnomad OTH exome AF: 0.0183

GnomAD4 exome AF: 0.0190 AC: 27809 AN: 1461756 Hom.: 320 Cov.: 33 AF XY: 0.0186 AC XY: 13497 AN XY: 727178

Gnomad4 AFR exome AF: 0.00338

Gnomad4 AMR exome AF: 0.0157

Gnomad4 ASJ exome AF: 0.0153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000742

Gnomad4 FIN exome AF: 0.0154

Gnomad4 NFE exome AF: 0.0221

Gnomad4 OTH exome AF: 0.0177

GnomAD4 genome AF: 0.0139 AC: 2111 AN: 152246 Hom.: 22 Cov.: 32 AF XY: 0.0139 AC XY: 1036 AN XY: 74424

Gnomad4 AFR AF: 0.00419

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.0165

Gnomad4 NFE AF: 0.0200

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0176 Hom.: 19

Bravo AF: 0.0147

TwinsUK AF: 0.0186 AC: 69

ALSPAC AF: 0.0215 AC: 83

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0217 AC: 187

ExAC AF: 0.0135 AC: 1635

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0213

EpiControl AF: 0.0214

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

REV3L-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 14, 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	0.17
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T;T;.;T
Eigen	Benign	-0.077
Eigen_PC	Benign	0.071
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0076	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	0.81	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.062
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.090	B;B;.;B
Vest4		0.16
MPC		0.076
ClinPred		0.0075	T
GERP RS		5.1
Varity_R		0.042
gMVP		0.32

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: rs3218599; hg19: chr6-111694124; COSMIC: COSV62618284;