6-111372921-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001372078.1(REV3L):​c.5434G>A​(p.Asp1812Asn) 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. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3893437).

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>A	p.Asp1812Asn	missense	Exon 13 of 32	NP_001359007.1	O60673-1
	REV3L	NM_002912.5		c.5434G>A	p.Asp1812Asn	missense	Exon 14 of 33	NP_002903.3	O60673-1
	REV3L	NM_001286431.2		c.5200G>A	p.Asp1734Asn	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>A	p.Asp1812Asn	missense	Exon 13 of 32	ENSP00000357792.3	O60673-1
	REV3L	ENST00000358835.7	TSL:5	c.5434G>A	p.Asp1812Asn	missense	Exon 14 of 33	ENSP00000351697.3	O60673-1
	REV3L	ENST00000435970.5	TSL:2	c.5200G>A	p.Asp1734Asn	missense	Exon 15 of 34	ENSP00000402003.1	O60673-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461776 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 19

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.084
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.92	T
PhyloP100		3.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.075
Sift	Benign	0.10	T
Sift4G	Benign	0.68	T
Polyphen		0.15	B
Vest4		0.62
MutPred		0.15		Gain of helix (P = 0.1736)
MVP		0.11
MPC		0.063
ClinPred		0.33	T
GERP RS		5.1
Varity_R		0.032
gMVP		0.24
Mutation Taster		=90/10	polymorphism

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;