Genetic Variant REV3L:p.Thr1224Ile (chr6-111374684-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001372078.1(REV3L):c.3671C>T(p.Thr1224Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.769 in 1,612,660 control chromosomes in the GnomAD database, including 486,868 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 0.67 ( 36564 hom., cov: 31)

Exomes 𝑓: 0.78 ( 450304 hom. )

Consequence

REV3L
NM_001372078.1 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.438

Publications

55 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=9.095963E-7).

BP6

Variant 6-111374684-G-A is Benign according to our data. Variant chr6-111374684-G-A is described in ClinVar as Benign. ClinVar VariationId is 3059806.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REV3L	NM_001372078.1 link	c.3671C>T	p.Thr1224Ile	missense_variant	Exon 13 of 32	ENST00000368802.8	NP_001359007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REV3L	ENST00000368802.8 link	c.3671C>T	p.Thr1224Ile	missense_variant	Exon 13 of 32	1	NM_001372078.1	ENSP00000357792.3		O60673-1

Frequencies

GnomAD3 genomes

AF:

0.673

AC:

102206

AN:

151876

Hom.:

36556

Cov.:

show subpopulations

Gnomad AFR

AF:

0.433

Gnomad AMI

AF:

0.738

Gnomad AMR

AF:

0.710

Gnomad ASJ

AF:

0.786

Gnomad EAS

AF:

0.445

Gnomad SAS

AF:

0.717

Gnomad FIN

AF:

0.694

Gnomad MID

AF:

0.744

Gnomad NFE

AF:

0.813

Gnomad OTH

AF:

0.713

GnomAD2 exomes

AF:

0.718

AC:

179543

AN:

250086

AF XY:

0.730

show subpopulations

Gnomad AFR exome

AF:

0.422

Gnomad AMR exome

AF:

0.677

Gnomad ASJ exome

AF:

0.784

Gnomad EAS exome

AF:

0.458

Gnomad FIN exome

AF:

0.704

Gnomad NFE exome

AF:

0.809

Gnomad OTH exome

AF:

0.763

GnomAD4 exome

AF:

0.779

AC:

1137992

AN:

1460666

Hom.:

450304

Cov.:

AF XY:

0.779

AC XY:

566158

AN XY:

726634

show subpopulations

African (AFR)

AF:

0.407

AC:

13594

AN:

33440

American (AMR)

AF:

0.687

AC:

30678

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.788

AC:

20576

AN:

26124

East Asian (EAS)

AF:

0.403

AC:

15983

AN:

39678

South Asian (SAS)

AF:

0.721

AC:

62138

AN:

86178

European-Finnish (FIN)

AF:

0.710

AC:

37635

AN:

52980

Middle Eastern (MID)

AF:

0.796

AC:

4590

AN:

5764

European-Non Finnish (NFE)

AF:

0.816

AC:

907106

AN:

1111456

Other (OTH)

AF:

0.757

AC:

45692

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

12823

25647

38470

51294

64117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20728

41456

62184

82912

103640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.673

AC:

102260

AN:

151994

Hom.:

36564

Cov.:

AF XY:

0.668

AC XY:

49639

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.434

AC:

17958

AN:

41422

American (AMR)

AF:

0.710

AC:

10845

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.786

AC:

2729

AN:

3470

East Asian (EAS)

AF:

0.445

AC:

2299

AN:

5168

South Asian (SAS)

AF:

0.717

AC:

3455

AN:

4820

European-Finnish (FIN)

AF:

0.694

AC:

7322

AN:

10552

Middle Eastern (MID)

AF:

0.752

AC:

221

AN:

294

European-Non Finnish (NFE)

AF:

0.813

AC:

55266

AN:

67972

Other (OTH)

AF:

0.709

AC:

1493

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1504

3009

4513

6018

7522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

794

1588

2382

3176

3970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.768

Hom.:

171402

Bravo

AF:

0.662

TwinsUK

AF:

0.816

AC:

3025

ALSPAC

AF:

0.818

AC:

3151

ESP6500AA

AF:

0.440

AC:

1939

ESP6500EA

AF:

0.813

AC:

6990

ExAC

AF:

0.715

AC:

86818

Asia WGS

AF:

0.590

AC:

2053

AN:

3478

EpiCase

AF:

0.820

EpiControl

AF:

0.820

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

REV3L-related disorder

Benign:1

Jun 06, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.65

(source)

DANN

Benign

0.10

DEOGEN2

Benign

0.050

T;T;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.11

.;.;T;T

MetaRNN

Benign

9.1e-7

T;T;T;T

MetaSVM

Benign

-0.99

PhyloP100

0.44

PrimateAI

Benign

0.29

PROVEAN

Benign

0.82

N;N;N;N

REVEL

Benign

0.050

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.35

T;T;T;T

Polyphen

0.0

B;B;.;B

Vest4

0.050

MPC

0.066

ClinPred

0.0063

GERP RS

1.4

Varity_R

0.018

gMVP

0.092

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over