6-111307423-C-T

Position:

• chr6-111307423-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

The ENST00000368802.8(REV3L):​c.9190G>A​(p.Val3064Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,613,776 control chromosomes in the GnomAD database, including 14,810 homozygotes. In-silico tool predicts 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 0.10 (1017 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13793 hom.)
• Consequence: REV3L ENST00000368802.8 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 7.69

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 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=0.0016376078).
• BP6: Variant 6-111307423-C-T is Benign according to our data. Variant chr6-111307423-C-T is described in ClinVar as [Benign]. Clinvar id is 1267973.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REV3L	NM_001372078.1	c.9190G>A	p.Val3064Ile	missense_variant	31/32	ENST00000368802.8	NP_001359007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REV3L	ENST00000368802.8	c.9190G>A	p.Val3064Ile	missense_variant	31/32	1	NM_001372078.1	ENSP00000357792	P4

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15317 AN: 152110 Hom.: 1019 Cov.: 32

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.0791

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0552

Gnomad FIN AF: 0.0993

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.104 AC: 26096 AN: 251464 Hom.: 1757 AF XY: 0.107 AC XY: 14533 AN XY: 135908

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.0842

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0536

Gnomad FIN exome AF: 0.0977

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.130 AC: 190234 AN: 1461548 Hom.: 13793 Cov.: 32 AF XY: 0.129 AC XY: 93774 AN XY: 727092

Gnomad4 AFR exome AF: 0.0220

Gnomad4 AMR exome AF: 0.0867

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0547

Gnomad4 FIN exome AF: 0.101

Gnomad4 NFE exome AF: 0.146

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.101 AC: 15302 AN: 152228 Hom.: 1017 Cov.: 32 AF XY: 0.0988 AC XY: 7354 AN XY: 74424

Gnomad4 AFR AF: 0.0253

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0549

Gnomad4 FIN AF: 0.0993

Gnomad4 NFE AF: 0.148

Gnomad4 OTH AF: 0.127

Alfa AF: 0.144 Hom.: 3583

Bravo AF: 0.100

TwinsUK AF: 0.145 AC: 538

ALSPAC AF: 0.146 AC: 564

ESP6500AA AF: 0.0259 AC: 114

ESP6500EA AF: 0.151 AC: 1296

ExAC AF: 0.102 AC: 12398

Asia WGS AF: 0.0320 AC: 112 AN: 3478

EpiCase AF: 0.167

EpiControl AF: 0.159

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

REV3L-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 17, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.094	T;T;.;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	.;.;D;D
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.00017	P;P;P;P
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.73	N;N;N;N
REVEL	Benign	0.079
Sift	Benign	0.038	D;D;D;D
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.39	B;B;.;B
Vest4		0.11
MPC		1.3
ClinPred		0.026	T
GERP RS		5.7
Varity_R		0.32
gMVP		0.58

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: rs3204953; hg19: chr6-111628626;