Genetic Variant NM_001371194.2:c.979G>A (chr9-89388764-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.979G>A(p.Ala327Thr) variant causes a missense change. The variant allele was found at a frequency of 0.282 in 1,607,020 control chromosomes in the GnomAD database, including 66,595 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.23 ( 4774 hom., cov: 33)

Exomes 𝑓: 0.29 ( 61821 hom. )

Consequence

SEMA4D
NM_001371194.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.76

Publications

35 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=0.002583325).

BP6

Variant 9-89388764-C-T is Benign according to our data. Variant chr9-89388764-C-T is described in ClinVar as Benign. ClinVar VariationId is 3060636.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4D	NM_001371194.2 link	c.979G>A	p.Ala327Thr	missense_variant	Exon 11 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.979G>A	p.Ala327Thr	missense_variant	Exon 11 of 16	1	NM_001371194.2	ENSP00000388768.2

Frequencies

GnomAD3 genomes

AF:

0.226

AC:

34369

AN:

152060

Hom.:

4772

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0561

Gnomad AMI

AF:

0.176

Gnomad AMR

AF:

0.255

Gnomad ASJ

AF:

0.209

Gnomad EAS

AF:

0.337

Gnomad SAS

AF:

0.266

Gnomad FIN

AF:

0.327

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.297

Gnomad OTH

AF:

0.255

GnomAD2 exomes

AF:

0.273

AC:

67540

AN:

247554

AF XY:

0.277

show subpopulations

Gnomad AFR exome

AF:

0.0511

Gnomad AMR exome

AF:

0.257

Gnomad ASJ exome

AF:

0.198

Gnomad EAS exome

AF:

0.335

Gnomad FIN exome

AF:

0.325

Gnomad NFE exome

AF:

0.296

Gnomad OTH exome

AF:

0.284

GnomAD4 exome

AF:

0.288

AC:

419505

AN:

1454842

Hom.:

61821

Cov.:

AF XY:

0.289

AC XY:

208678

AN XY:

722676

show subpopulations

African (AFR)

AF:

0.0470

AC:

1565

AN:

33326

American (AMR)

AF:

0.262

AC:

11590

AN:

44268

Ashkenazi Jewish (ASJ)

AF:

0.198

AC:

5145

AN:

25948

East Asian (EAS)

AF:

0.365

AC:

14445

AN:

39554

South Asian (SAS)

AF:

0.269

AC:

23175

AN:

86138

European-Finnish (FIN)

AF:

0.318

AC:

16564

AN:

52074

Middle Eastern (MID)

AF:

0.223

AC:

1283

AN:

5742

European-Non Finnish (NFE)

AF:

0.297

AC:

329516

AN:

1107790

Other (OTH)

AF:

0.270

AC:

16222

AN:

60002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

17478

34956

52433

69911

87389

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10800

21600

32400

43200

54000

<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:

0.226

AC:

34365

AN:

152178

Hom.:

4774

Cov.:

AF XY:

0.228

AC XY:

16944

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0560

AC:

2325

AN:

41544

American (AMR)

AF:

0.254

AC:

3886

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.209

AC:

724

AN:

3472

East Asian (EAS)

AF:

0.336

AC:

1743

AN:

5184

South Asian (SAS)

AF:

0.265

AC:

1274

AN:

4816

European-Finnish (FIN)

AF:

0.327

AC:

3464

AN:

10590

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.297

AC:

20194

AN:

67974

Other (OTH)

AF:

0.260

AC:

550

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1310

2620

3931

5241

6551

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

370

740

1110

1480

1850

<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:

0.278

Hom.:

19862

Bravo

AF:

0.214

TwinsUK

AF:

0.285

AC:

1057

ALSPAC

AF:

0.287

AC:

1108

ESP6500AA

AF:

0.0631

AC:

278

ESP6500EA

AF:

0.289

AC:

2486

ExAC

AF:

0.270

AC:

32819

Asia WGS

AF:

0.272

AC:

945

AN:

3478

EpiCase

AF:

0.292

EpiControl

AF:

0.300

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

SEMA4D-related disorder

Benign:1

Oct 21, 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

0.12

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.27

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

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.62

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

MetaRNN

Benign

0.0026

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

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.5

M;M;M;M;M;M;M

PhyloP100

3.8

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.8

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

REVEL

Benign

0.29

Sift

Benign

0.069

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

Sift4G

Uncertain

0.047

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

Polyphen

1.0

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

Vest4

0.44

MPC

0.69

ClinPred

0.020

GERP RS

4.0

Varity_R

0.64

gMVP

0.66

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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