rs281294

Variant names:

• chr15-47391449-A-G
• rs281294
• ENST00000558014.5:c.-238-20944A>G

Variant summary

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

The ENST00000558014.5(SEMA6D):​c.-238-20944A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 151,944 control chromosomes in the GnomAD database, including 8,926 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 0.28 (8926 hom., cov: 32)
• Consequence: SEMA6D ENST00000558014.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.27
• Publications: 1 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6D	NM_001198999.2	c.-238-20944A>G		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.-238-20944A>G		intron_variant	Intron 1 of 19	1		ENSP00000452815.1
SEMA6D	ENST00000559184.5	c.-238-20944A>G		intron_variant	Intron 2 of 5	4		ENSP00000453097.1
SEMA6D	ENST00000560636.5	c.-322-20944A>G		intron_variant	Intron 1 of 5	4		ENSP00000453420.1

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42859 AN: 151826 Hom.: 8884 Cov.: 32

Gnomad AFR AF: 0.573

Gnomad AMI AF: 0.165

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.0930

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.252

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

GnomAD4 genome AF: 0.283 AC: 42973 AN: 151944 Hom.: 8926 Cov.: 32 AF XY: 0.280 AC XY: 20774 AN XY: 74292

African (AFR) AF: 0.573 AC: 23733 AN: 41412

American (AMR) AF: 0.239 AC: 3649 AN: 15248

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

East Asian (EAS) AF: 0.441 AC: 2254 AN: 5116

South Asian (SAS) AF: 0.261 AC: 1259 AN: 4818

European-Finnish (FIN) AF: 0.0930 AC: 985 AN: 10586

Middle Eastern (MID) AF: 0.234 AC: 68 AN: 290

European-Non Finnish (NFE) AF: 0.141 AC: 9555 AN: 67984

Other (OTH) AF: 0.261 AC: 550 AN: 2110

Alfa AF: 0.183 Hom.: 1146

Bravo AF: 0.306

Asia WGS AF: 0.423 AC: 1469 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.0020
DANN	Benign	0.37
PhyloP100		-4.3
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: rs281294; hg19: chr15-47683646;