6-111372921-C-G

Variant names:

• chr6-111372921-C-G
• rs3218599
• NM_001372078.1:c.5434G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.014 (22 hom., cov: 32)
  • Exomes 𝑓: 0.019 (320 hom.)
• Consequence: REV3L NM_001372078.1 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.43
• Publications: 16 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• 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 VariationId is 3041876.Status of the report is no_assertion_criteria_provided, 0 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2111 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372078.1. 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
	REV3L	NM_001372078.1	MANE Select	c.5434G>C	p.Asp1812His	missense	Exon 13 of 32	NP_001359007.1	O60673-1
	REV3L	NM_002912.5		c.5434G>C	p.Asp1812His	missense	Exon 14 of 33	NP_002903.3	O60673-1
	REV3L	NM_001286431.2		c.5200G>C	p.Asp1734His	missense	Exon 16 of 35	NP_001273360.1	O60673-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REV3L	ENST00000368802.8	TSL:1 MANE Select	c.5434G>C	p.Asp1812His	missense	Exon 13 of 32	ENSP00000357792.3	O60673-1
	REV3L	ENST00000358835.7	TSL:5	c.5434G>C	p.Asp1812His	missense	Exon 14 of 33	ENSP00000351697.3	O60673-1
	REV3L	ENST00000435970.5	TSL:2	c.5200G>C	p.Asp1734His	missense	Exon 15 of 34	ENSP00000402003.1	O60673-2

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

GnomAD2 exomes AF: 0.0142 AC: 3561 AN: 251326 AF XY: 0.0140

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 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

African (AFR) AF: 0.00338 AC: 113 AN: 33478

American (AMR) AF: 0.0157 AC: 703 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 400 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000742 AC: 64 AN: 86244

European-Finnish (FIN) AF: 0.0154 AC: 824 AN: 53360

Middle Eastern (MID) AF: 0.00936 AC: 54 AN: 5768

European-Non Finnish (NFE) AF: 0.0221 AC: 24583 AN: 1111962

Other (OTH) AF: 0.0177 AC: 1068 AN: 60392

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

African (AFR) AF: 0.00419 AC: 174 AN: 41560

American (AMR) AF: 0.0184 AC: 281 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4808

European-Finnish (FIN) AF: 0.0165 AC: 175 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0200 AC: 1359 AN: 68012

Other (OTH) AF: 0.0218 AC: 46 AN: 2112

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

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	REV3L-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.077
Eigen_PC	Benign	0.071
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.89	T
PhyloP100		3.4
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.062
Sift	Benign	0.14	T
Sift4G	Benign	0.32	T
Polyphen		0.090	B
Vest4		0.16
MPC		0.076
ClinPred		0.0075	T
GERP RS		5.1
Varity_R		0.042
gMVP		0.32
Mutation Taster		=100/0	polymorphism (auto)

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