Genetic Variant SEMA6D:p.Ala407Ala (chr15-47764761-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_001358351.3(SEMA6D):c.1221C>T(p.Ala407Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,613,698 control chromosomes in the GnomAD database, including 53,344 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 3650 hom., cov: 33)

Exomes 𝑓: 0.26 ( 49694 hom. )

Consequence

SEMA6D
NM_001358351.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.17

Publications

16 publications found

Variant links:

Genes affected

SEMA6D (HGNC:16770): (semaphorin 6D) Semaphorins are a large family, including both secreted and membrane associated proteins, many of which have been implicated as inhibitors or chemorepellents in axon pathfinding, fasciculation and branching, and target selection. All semaphorins possess a semaphorin (Sema) domain and a PSI domain (found in plexins, semaphorins and integrins) in the N-terminal extracellular portion. Additional sequence motifs C-terminal to the semaphorin domain allow classification into distinct subfamilies. Results demonstrate that transmembrane semaphorins, like the secreted ones, can act as repulsive axon guidance cues. This gene encodes a class 6 vertebrate transmembrane semaphorin that demonstrates alternative splicing. Several transcript variants have been identified and expression of the distinct encoded isoforms is thought to be regulated in a tissue- and development-dependent manner. [provided by RefSeq, Nov 2010]

SEMA6D Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

SEMA6D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BP7

Synonymous conserved (PhyloP=-1.17 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6D	NM_001358351.3 link	c.1221C>T	p.Ala407Ala	synonymous_variant	Exon 12 of 19	ENST00000536845.7	NP_001345280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA6D	ENST00000536845.7 link	c.1221C>T	p.Ala407Ala	synonymous_variant	Exon 12 of 19	2	NM_001358351.3	ENSP00000446152.3		Q8NFY4-1

Frequencies

GnomAD3 genomes

AF:

0.201

AC:

30584

AN:

152048

Hom.:

3649

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0683

Gnomad AMI

AF:

0.279

Gnomad AMR

AF:

0.200

Gnomad ASJ

AF:

0.223

Gnomad EAS

AF:

0.186

Gnomad SAS

AF:

0.312

Gnomad FIN

AF:

0.319

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.255

Gnomad OTH

AF:

0.207

GnomAD2 exomes

AF:

0.244

AC:

61143

AN:

251024

AF XY:

0.252

show subpopulations

Gnomad AFR exome

AF:

0.0673

Gnomad AMR exome

AF:

0.192

Gnomad ASJ exome

AF:

0.220

Gnomad EAS exome

AF:

0.191

Gnomad FIN exome

AF:

0.327

Gnomad NFE exome

AF:

0.261

Gnomad OTH exome

AF:

0.247

GnomAD4 exome

AF:

0.257

AC:

375103

AN:

1461532

Hom.:

49694

Cov.:

AF XY:

0.259

AC XY:

188539

AN XY:

727068

show subpopulations

African (AFR)

AF:

0.0612

AC:

2049

AN:

33466

American (AMR)

AF:

0.194

AC:

8670

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.218

AC:

5691

AN:

26126

East Asian (EAS)

AF:

0.208

AC:

8236

AN:

39668

South Asian (SAS)

AF:

0.307

AC:

26455

AN:

86246

European-Finnish (FIN)

AF:

0.320

AC:

17116

AN:

53412

Middle Eastern (MID)

AF:

0.204

AC:

1177

AN:

5764

European-Non Finnish (NFE)

AF:

0.262

AC:

291010

AN:

1111752

Other (OTH)

AF:

0.243

AC:

14699

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

15540

31079

46619

62158

77698

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9830

19660

29490

39320

49150

<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:

0.201

AC:

30597

AN:

152166

Hom.:

3650

Cov.:

AF XY:

0.207

AC XY:

15372

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0683

AC:

2838

AN:

41562

American (AMR)

AF:

0.201

AC:

3074

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.223

AC:

772

AN:

3466

East Asian (EAS)

AF:

0.187

AC:

966

AN:

5168

South Asian (SAS)

AF:

0.311

AC:

1497

AN:

4820

European-Finnish (FIN)

AF:

0.319

AC:

3377

AN:

10570

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.255

AC:

17338

AN:

67972

Other (OTH)

AF:

0.205

AC:

433

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1230

2461

3691

4922

6152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

346

692

1038

1384

1730

<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:

0.234

Hom.:

8652

Bravo

AF:

0.185

Asia WGS

AF:

0.232

AC:

806

AN:

3478

EpiCase

AF:

0.247

EpiControl

AF:

0.250

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

1.3

(source)

DANN

Benign

0.82

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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