6-111309969-G-T

Variant names:

• chr6-111309969-G-T
• rs143815049
• NM_001372078.1:c.8926C>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.8926C>A​(p.Pro2976Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. P2976S) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: REV3L NM_001372078.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.66
• Publications: 0 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]

ENSG00000272356 (HGNC:58340):

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=0.29305613).

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.8926C>A	p.Pro2976Thr	missense	Exon 30 of 32	NP_001359007.1	O60673-1
	REV3L	NM_002912.5		c.8926C>A	p.Pro2976Thr	missense	Exon 31 of 33	NP_002903.3	O60673-1
	REV3L	NM_001286431.2		c.8692C>A	p.Pro2898Thr	missense	Exon 33 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.8926C>A	p.Pro2976Thr	missense	Exon 30 of 32	ENSP00000357792.3	O60673-1
	REV3L	ENST00000462119.5	TSL:1	n.831C>A		non_coding_transcript_exon	Exon 4 of 7
	REV3L	ENST00000358835.7	TSL:5	c.8926C>A	p.Pro2976Thr	missense	Exon 31 of 33	ENSP00000351697.3	O60673-1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74260

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000242 AC: 1 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2078

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.032
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
PhyloP100		4.7
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.066
Sift	Benign	0.036	D
Sift4G	Benign	0.069	T
Polyphen		0.015	B
Vest4		0.27
MutPred		0.54		Gain of catalytic residue at P2976 (P = 0.0393)
MVP		0.19
MPC		0.74
ClinPred		0.89	D
GERP RS		4.6
Varity_R		0.17
gMVP		0.58
Mutation Taster		=62/38	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: rs143815049; hg19: chr6-111631172;