Genetic Variant SEMA4D:p.Ala72Thr (chr9-89402909-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

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

The NM_001371194.2(SEMA4D):c.214G>A(p.Ala72Thr) variant causes a missense change. The variant allele was found at a frequency of 0.045 in 1,613,980 control chromosomes in the GnomAD database, including 1,945 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.034 ( 127 hom., cov: 32)

Exomes 𝑓: 0.046 ( 1818 hom. )

Consequence

SEMA4D
NM_001371194.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 5.47

Publications

14 publications found

Variant links:

Genes affected

SEMA4D (HGNC:10732): (semaphorin 4D) Enables identical protein binding activity; semaphorin receptor binding activity; and transmembrane signaling receptor activity. Involved in several processes, including positive regulation of phosphatidylinositol 3-kinase signaling; regulation of neuron projection development; and regulation of phosphate metabolic process. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SEMA4D 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=0.010484457).

BP6

Variant 9-89402909-C-T is Benign according to our data. Variant chr9-89402909-C-T is described in ClinVar as Benign. ClinVar VariationId is 3055397.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4D	NM_001371194.2 link	c.214G>A	p.Ala72Thr	missense_variant	Exon 4 of 16	ENST00000422704.7	NP_001358123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA4D	ENST00000422704.7 link	c.214G>A	p.Ala72Thr	missense_variant	Exon 4 of 16	1	NM_001371194.2	ENSP00000388768.2

Frequencies

GnomAD3 genomes

AF:

0.0335

AC:

5103

AN:

152128

Hom.:

127

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00893

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.0321

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.0751

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0475

Gnomad OTH

AF:

0.0258

GnomAD2 exomes

AF:

0.0357

AC:

8970

AN:

251412

AF XY:

0.0359

show subpopulations

Gnomad AFR exome

AF:

0.00812

Gnomad AMR exome

AF:

0.0315

Gnomad ASJ exome

AF:

0.0127

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0724

Gnomad NFE exome

AF:

0.0461

Gnomad OTH exome

AF:

0.0380

GnomAD4 exome

AF:

0.0462

AC:

67480

AN:

1461734

Hom.:

1818

Cov.:

AF XY:

0.0453

AC XY:

32908

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.00654

AC:

219

AN:

33480

American (AMR)

AF:

0.0311

AC:

1392

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0132

AC:

345

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39698

South Asian (SAS)

AF:

0.0188

AC:

1623

AN:

86258

European-Finnish (FIN)

AF:

0.0726

AC:

3878

AN:

53388

Middle Eastern (MID)

AF:

0.00850

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0519

AC:

57693

AN:

1111896

Other (OTH)

AF:

0.0377

AC:

2277

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

3322

6644

9966

13288

16610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2130

4260

6390

8520

10650

<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:

0.0335

AC:

5106

AN:

152246

Hom.:

127

Cov.:

AF XY:

0.0342

AC XY:

2542

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00890

AC:

370

AN:

41550

American (AMR)

AF:

0.0321

AC:

492

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3470

East Asian (EAS)

AF:

0.00135

AC:

AN:

5176

South Asian (SAS)

AF:

0.0170

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0751

AC:

795

AN:

10588

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0475

AC:

3228

AN:

68014

Other (OTH)

AF:

0.0260

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

253

507

760

1014

1267

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0401

Hom.:

496

Bravo

AF:

0.0294

TwinsUK

AF:

0.0491

AC:

182

ALSPAC

AF:

0.0490

AC:

189

ESP6500AA

AF:

0.00794

AC:

ESP6500EA

AF:

0.0435

AC:

374

ExAC

AF:

0.0340

AC:

4134

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0410

EpiControl

AF:

0.0431

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

SEMA4D-related disorder

Benign:1

Oct 17, 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

0.17

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;.;.;T;T;T;T;.;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.69

.;T;.;.;.;T;.;T;T

MetaRNN

Benign

0.010

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;M;M;M;M;M;M;.;.

PhyloP100

5.5

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.7

D;D;D;D;D;D;D;D;D

REVEL

Benign

0.14

Sift

Uncertain

0.0090

D;D;D;D;D;D;D;T;T

Sift4G

Uncertain

0.0070

D;D;D;D;D;D;D;.;.

Polyphen

0.72

P;P;P;P;P;P;P;.;.

Vest4

0.36

MPC

0.65

ClinPred

0.049

GERP RS

4.8

Varity_R

0.77

gMVP

0.50

Mutation Taster

=98/2

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