rs586799

Variant names:

• chr15-47732725-A-G
• rs586799
• NM_001358351.3:c.-55+15033A>G

Variant summary

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

The NM_001358351.3(SEMA6D):​c.-55+15033A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 152,098 control chromosomes in the GnomAD database, including 7,940 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 0.29 (7940 hom., cov: 33)
• Consequence: SEMA6D NM_001358351.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.766
• Publications: 3 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001358351.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA6D	NM_001358351.3	MANE Select	c.-55+15033A>G		intron	N/A	NP_001345280.1	Q8NFY4-1
	SEMA6D	NM_001358352.2		c.-55+15033A>G		intron	N/A	NP_001345281.1
	SEMA6D	NM_153618.2		c.-55+13852A>G		intron	N/A	NP_705871.1	Q8NFY4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA6D	ENST00000536845.7	TSL:2 MANE Select	c.-55+15033A>G		intron	N/A	ENSP00000446152.3	Q8NFY4-1
	SEMA6D	ENST00000316364.9	TSL:1	c.-55+13852A>G		intron	N/A	ENSP00000324857.5	Q8NFY4-1
	SEMA6D	ENST00000354744.8	TSL:1	c.-55+13852A>G		intron	N/A	ENSP00000346786.4	Q8NFY4-4

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44238 AN: 151982 Hom.: 7941 Cov.: 33

Gnomad AFR AF: 0.0774

Gnomad AMI AF: 0.476

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.319

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

GnomAD4 genome AF: 0.291 AC: 44230 AN: 152098 Hom.: 7940 Cov.: 33 AF XY: 0.286 AC XY: 21273 AN XY: 74344

African (AFR) AF: 0.0771 AC: 3205 AN: 41552

American (AMR) AF: 0.353 AC: 5388 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1361 AN: 3466

East Asian (EAS) AF: 0.280 AC: 1445 AN: 5168

South Asian (SAS) AF: 0.286 AC: 1375 AN: 4806

European-Finnish (FIN) AF: 0.311 AC: 3285 AN: 10558

Middle Eastern (MID) AF: 0.394 AC: 115 AN: 292

European-Non Finnish (NFE) AF: 0.397 AC: 26960 AN: 67960

Other (OTH) AF: 0.314 AC: 663 AN: 2112

Alfa AF: 0.371 Hom.: 6719

Bravo AF: 0.288

Asia WGS AF: 0.248 AC: 862 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.3
DANN	Benign	0.65
PhyloP100		0.77
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs586799; hg19: chr15-48024922;