Genetic Variant NM_001372078.1:c.3671C>A (chr6-111374684-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001372078.1(REV3L):c.3671C>A(p.Thr1224Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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. T1224I) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

REV3L
NM_001372078.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.438

Publications

0 publications found

Variant links:

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]

REV3L links:

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]

MFSD4B links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040053636).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
REV3L	NM_001372078.1	MANE Select	c.3671C>A	p.Thr1224Lys	missense	Exon 13 of 32	NP_001359007.1	O60673-1
REV3L	NM_002912.5		c.3671C>A	p.Thr1224Lys	missense	Exon 14 of 33	NP_002903.3	O60673-1
REV3L	NM_001286431.2		c.3437C>A	p.Thr1146Lys	missense	Exon 16 of 35	NP_001273360.1	O60673-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
REV3L	ENST00000368802.8	TSL:1 MANE Select	c.3671C>A	p.Thr1224Lys	missense	Exon 13 of 32	ENSP00000357792.3	O60673-1
REV3L	ENST00000358835.7	TSL:5	c.3671C>A	p.Thr1224Lys	missense	Exon 14 of 33	ENSP00000351697.3	O60673-1
REV3L	ENST00000435970.5	TSL:2	c.3437C>A	p.Thr1146Lys	missense	Exon 15 of 34	ENSP00000402003.1	O60673-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726906

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53010

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111892

Other (OTH)

AF:

0.00

AC:

AN:

60384

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

1.5

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.076

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.11

M_CAP

Benign

0.011

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.94

PhyloP100

0.44

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.44

REVEL

Benign

0.052

Sift

Uncertain

0.0050

Sift4G

Benign

0.96

Polyphen

0.012

Vest4

0.13

MutPred

0.17

Loss of phosphorylation at T1224 (P = 0.0281)

MVP

0.043

MPC

0.074

ClinPred

0.068

GERP RS

1.4

Varity_R

0.041

gMVP

0.24

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over