rs3218599

chr6-111372921-C-Achr6-111372921-C-Gchr6-111372921-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001372078.1(REV3L):c.5434G>T(p.Asp1812Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1812H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: REV3L NM_001372078.1 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, REV3L

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REV3L	NM_001372078.1	c.5434G>T	p.Asp1812Tyr	missense_variant	13/32	ENST00000368802.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REV3L	ENST00000368802.8	c.5434G>T	p.Asp1812Tyr	missense_variant	13/32	1	NM_001372078.1	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251326 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461776 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.16	T;T;.;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.50	D;D;D;D
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	0.89	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N;N;D;N
REVEL	Benign	0.099
Sift	Uncertain	0.015	D;D;D;D
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.91	P;P;.;P
Vest4		0.81
MutPred		0.33		Loss of disorder (P = 0.025);Loss of disorder (P = 0.025);.;Loss of disorder (P = 0.025);
MVP		0.26
MPC		0.17
ClinPred		0.43	T
GERP RS		5.1
Varity_R		0.080
gMVP		0.37

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;