Genetic Variant SEMA6D:c.-238-23223G>A (chr15-47389170-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000558014.5(SEMA6D):c.-238-23223G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 151,922 control chromosomes in the GnomAD database, including 3,913 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 0.22 ( 3913 hom., cov: 32)

Consequence

SEMA6D
ENST00000558014.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0140

Publications

3 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:

ENSG00000259221 (HGNC:):

ENSG00000259221 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 (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6D	NM_001198999.2 link	c.-238-23223G>A		intron_variant	Intron 1 of 19		NP_001185928.1	Q8NFY4-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
SEMA6D	ENST00000558014.5 link	c.-238-23223G>A	intron_variant	Intron 1 of 19	1	ENSP00000452815.1	Q8NFY4-2
SEMA6D	ENST00000559184.5 link	c.-238-23223G>A	intron_variant	Intron 2 of 5	4	ENSP00000453097.1	H0YL82
SEMA6D	ENST00000560636.5 link	c.-322-23223G>A	intron_variant	Intron 1 of 5	4	ENSP00000453420.1

Frequencies

GnomAD3 genomes

AF:

0.219

AC:

33237

AN:

151804

Hom.:

3911

Cov.:

show subpopulations

Gnomad AFR

AF:

0.267

Gnomad AMI

AF:

0.185

Gnomad AMR

AF:

0.228

Gnomad ASJ

AF:

0.174

Gnomad EAS

AF:

0.0407

Gnomad SAS

AF:

0.0941

Gnomad FIN

AF:

0.213

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.213

Gnomad OTH

AF:

0.235

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.219

AC:

33260

AN:

151922

Hom.:

3913

Cov.:

AF XY:

0.215

AC XY:

15944

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.267

AC:

11072

AN:

41446

American (AMR)

AF:

0.228

AC:

3474

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.174

AC:

602

AN:

3468

East Asian (EAS)

AF:

0.0408

AC:

211

AN:

5168

South Asian (SAS)

AF:

0.0948

AC:

456

AN:

4810

European-Finnish (FIN)

AF:

0.213

AC:

2248

AN:

10530

Middle Eastern (MID)

AF:

0.333

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.213

AC:

14440

AN:

67922

Other (OTH)

AF:

0.232

AC:

490

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1295

2590

3886

5181

6476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.0746

Hom.:

104

Bravo

AF:

0.223

Asia WGS

AF:

0.0810

AC:

282

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.7

(source)

DANN

Benign

0.57

PhyloP100

-0.014

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over