Genetic Variant NM_001031746.5:c.203T>C (chr10-49107848-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001031746.5(VSTM4):c.203T>C(p.Phe68Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 1,613,938 control chromosomes in the GnomAD database, including 142,856 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F68F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.48 ( 19390 hom., cov: 33)

Exomes 𝑓: 0.41 ( 123466 hom. )

Consequence

VSTM4
NM_001031746.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.870

Publications

33 publications found

Variant links:

Genes affected

VSTM4 (HGNC:26470): (V-set and transmembrane domain containing 4) Predicted to act upstream of or within several processes, including endothelial cell migration; retina blood vessel maintenance; and vasculature development. Predicted to be located in extracellular region and plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

VSTM4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.616328E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSTM4	NM_001031746.5 link	c.203T>C	p.Phe68Ser	missense_variant	Exon 2 of 8	ENST00000332853.9	NP_001026916.2	Q8IW00-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VSTM4	ENST00000332853.9 link	c.203T>C	p.Phe68Ser	missense_variant	Exon 2 of 8	1	NM_001031746.5	ENSP00000331062.3		Q8IW00-1
VSTM4	ENST00000298454.3 link	c.203T>C	p.Phe68Ser	missense_variant	Exon 2 of 3	2		ENSP00000298454.3		Q8IW00-2

Frequencies

GnomAD3 genomes

AF:

0.485

AC:

73668

AN:

151992

Hom.:

19362

Cov.:

show subpopulations

Gnomad AFR

AF:

0.704

Gnomad AMI

AF:

0.433

Gnomad AMR

AF:

0.466

Gnomad ASJ

AF:

0.450

Gnomad EAS

AF:

0.219

Gnomad SAS

AF:

0.475

Gnomad FIN

AF:

0.366

Gnomad MID

AF:

0.415

Gnomad NFE

AF:

0.398

Gnomad OTH

AF:

0.463

GnomAD2 exomes

AF:

0.423

AC:

106238

AN:

251230

AF XY:

0.420

show subpopulations

Gnomad AFR exome

AF:

0.710

Gnomad AMR exome

AF:

0.446

Gnomad ASJ exome

AF:

0.447

Gnomad EAS exome

AF:

0.207

Gnomad FIN exome

AF:

0.372

Gnomad NFE exome

AF:

0.401

Gnomad OTH exome

AF:

0.415

GnomAD4 exome

AF:

0.405

AC:

592248

AN:

1461826

Hom.:

123466

Cov.:

AF XY:

0.407

AC XY:

295650

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.714

AC:

23912

AN:

33480

American (AMR)

AF:

0.446

AC:

19959

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.444

AC:

11592

AN:

26136

East Asian (EAS)

AF:

0.220

AC:

8746

AN:

39698

South Asian (SAS)

AF:

0.479

AC:

41304

AN:

86258

European-Finnish (FIN)

AF:

0.376

AC:

20101

AN:

53404

Middle Eastern (MID)

AF:

0.434

AC:

2506

AN:

5768

European-Non Finnish (NFE)

AF:

0.395

AC:

439249

AN:

1111974

Other (OTH)

AF:

0.412

AC:

24879

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

25209

50418

75627

100836

126045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13766

27532

41298

55064

68830

<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:

0.485

AC:

73753

AN:

152112

Hom.:

19390

Cov.:

AF XY:

0.483

AC XY:

35923

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.704

AC:

29226

AN:

41512

American (AMR)

AF:

0.466

AC:

7124

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.450

AC:

1559

AN:

3468

East Asian (EAS)

AF:

0.219

AC:

1133

AN:

5164

South Asian (SAS)

AF:

0.475

AC:

2291

AN:

4822

European-Finnish (FIN)

AF:

0.366

AC:

3873

AN:

10574

Middle Eastern (MID)

AF:

0.398

AC:

117

AN:

294

European-Non Finnish (NFE)

AF:

0.398

AC:

27072

AN:

67966

Other (OTH)

AF:

0.458

AC:

964

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1851

3702

5554

7405

9256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

636

1272

1908

2544

3180

<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:

0.426

Hom.:

49838

Bravo

AF:

0.497

TwinsUK

AF:

0.389

AC:

1441

ALSPAC

AF:

0.394

AC:

1519

ESP6500AA

AF:

0.708

AC:

3121

ESP6500EA

AF:

0.393

AC:

3376

ExAC

AF:

0.429

AC:

52136

Asia WGS

AF:

0.396

AC:

1375

AN:

3478

EpiCase

AF:

0.395

EpiControl

AF:

0.405

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.032

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

4.4

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.0041

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0097

LIST_S2

Benign

0.26

T;T

MetaRNN

Benign

0.0000026

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

N;N

PhyloP100

0.87

PrimateAI

Benign

0.30

PROVEAN

Benign

2.9

N;N

REVEL

Benign

0.043

Sift

Benign

0.97

T;T

Sift4G

Benign

0.77

T;T

Polyphen

0.0

B;B

Vest4

0.037

MPC

0.29

ClinPred

0.00051

GERP RS

1.8

Varity_R

0.025

gMVP

0.38

Mutation Taster

=99/1

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

Computational scores

Splicing

Publications

Other links and lift over