rs12593270

Variant names:

• chr15-47455143-G-C
• rs12593270
• ENST00000558014.5:c.-158-15331G>C

Variant summary

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

The ENST00000558014.5(SEMA6D):​c.-158-15331G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 151,350 control chromosomes in the GnomAD database, including 3,876 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 (3876 hom., cov: 31)
• Consequence: SEMA6D ENST00000558014.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.222
• Publications: 0 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6D	NM_001198999.2	c.-158-15331G>C		intron_variant	Intron 2 of 19		NP_001185928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA6D	ENST00000558014.5	c.-158-15331G>C		intron_variant	Intron 2 of 19	1		ENSP00000452815.1
SEMA6D	ENST00000559184.5	c.-158-15331G>C		intron_variant	Intron 3 of 5	4		ENSP00000453097.1
SEMA6D	ENST00000560636.5	c.-242-15331G>C		intron_variant	Intron 2 of 5	4		ENSP00000453420.1

Frequencies

GnomAD3 genomes AF: 0.224 AC: 33918 AN: 151242 Hom.: 3876 Cov.: 31

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.364

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.217

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

GnomAD4 genome AF: 0.224 AC: 33932 AN: 151350 Hom.: 3876 Cov.: 31 AF XY: 0.229 AC XY: 16933 AN XY: 73906

African (AFR) AF: 0.197 AC: 8153 AN: 41298

American (AMR) AF: 0.180 AC: 2728 AN: 15142

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 770 AN: 3464

East Asian (EAS) AF: 0.239 AC: 1215 AN: 5094

South Asian (SAS) AF: 0.364 AC: 1738 AN: 4780

European-Finnish (FIN) AF: 0.294 AC: 3086 AN: 10498

Middle Eastern (MID) AF: 0.151 AC: 44 AN: 292

European-Non Finnish (NFE) AF: 0.229 AC: 15542 AN: 67772

Other (OTH) AF: 0.213 AC: 446 AN: 2098

Alfa AF: 0.221 Hom.: 504

Bravo AF: 0.214

Asia WGS AF: 0.259 AC: 903 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.6
DANN	Benign	0.52
PhyloP100		-0.22
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: rs12593270; hg19: chr15-47747340;