rs281282

Variant names:

• chr15-47387060-G-A
• rs281282
• ENST00000558014.5:c.-238-25333G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000558014.5(SEMA6D):​c.-238-25333G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 152,074 control chromosomes in the GnomAD database, including 7,606 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 0.27 (7606 hom., cov: 32)
• Consequence: SEMA6D ENST00000558014.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45
• Publications: 6 publications found

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

ENSG00000259221 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6D	NM_001198999.2	c.-238-25333G>A		intron_variant	Intron 1 of 19		NP_001185928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA6D	ENST00000558014.5	c.-238-25333G>A		intron_variant	Intron 1 of 19	1		ENSP00000452815.1
SEMA6D	ENST00000559184.5	c.-238-25333G>A		intron_variant	Intron 2 of 5	4		ENSP00000453097.1
SEMA6D	ENST00000560636.5	c.-322-25333G>A		intron_variant	Intron 1 of 5	4		ENSP00000453420.1

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40438 AN: 151956 Hom.: 7569 Cov.: 32

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.0928

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.238

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

GnomAD4 genome AF: 0.267 AC: 40545 AN: 152074 Hom.: 7606 Cov.: 32 AF XY: 0.264 AC XY: 19632 AN XY: 74342

African (AFR) AF: 0.515 AC: 21369 AN: 41470

American (AMR) AF: 0.235 AC: 3593 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 770 AN: 3472

East Asian (EAS) AF: 0.447 AC: 2298 AN: 5142

South Asian (SAS) AF: 0.262 AC: 1258 AN: 4810

European-Finnish (FIN) AF: 0.0928 AC: 984 AN: 10600

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.140 AC: 9530 AN: 67990

Other (OTH) AF: 0.247 AC: 522 AN: 2114

Alfa AF: 0.179 Hom.: 5309

Bravo AF: 0.287

Asia WGS AF: 0.422 AC: 1466 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.12
DANN	Benign	0.56
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs281282; hg19: chr15-47679257;