15-47757579-C-T

Variant names:

• chr15-47757579-C-T
• rs586118
• NM_001358351.3:c.-54-2166C>T

Variant summary

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

The NM_001358352.2(SEMA6D):​c.-54-2166C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 151,884 control chromosomes in the GnomAD database, including 21,375 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 0.49 (21375 hom., cov: 32)
• Consequence: SEMA6D NM_001358352.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.612
• 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 (AFR) allele frequency at 95% confidence interval = 0.769 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001358352.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA6D	NM_001358351.3	MANE Select	c.-54-2166C>T		intron	N/A	NP_001345280.1
	SEMA6D	NM_001358352.2		c.-54-2166C>T		intron	N/A	NP_001345281.1
	SEMA6D	NM_153618.2		c.-54-2166C>T		intron	N/A	NP_705871.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA6D	ENST00000536845.7	TSL:2 MANE Select	c.-54-2166C>T		intron	N/A	ENSP00000446152.3
	SEMA6D	ENST00000316364.9	TSL:1	c.-54-2166C>T		intron	N/A	ENSP00000324857.5
	SEMA6D	ENST00000354744.8	TSL:1	c.-54-2166C>T		intron	N/A	ENSP00000346786.4

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74737 AN: 151766 Hom.: 21316 Cov.: 32

Gnomad AFR AF: 0.776

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.531

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.458

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

GnomAD4 genome AF: 0.493 AC: 74863 AN: 151884 Hom.: 21375 Cov.: 32 AF XY: 0.499 AC XY: 37056 AN XY: 74240

African (AFR) AF: 0.776 AC: 32188 AN: 41456

American (AMR) AF: 0.448 AC: 6841 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1086 AN: 3466

East Asian (EAS) AF: 0.710 AC: 3658 AN: 5150

South Asian (SAS) AF: 0.529 AC: 2547 AN: 4814

European-Finnish (FIN) AF: 0.431 AC: 4529 AN: 10514

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22551 AN: 67908

Other (OTH) AF: 0.464 AC: 980 AN: 2110

Alfa AF: 0.202 Hom.: 362

Bravo AF: 0.508

Asia WGS AF: 0.656 AC: 2278 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.88
DANN	Benign	0.51
PhyloP100		-0.61
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: rs586118; hg19: chr15-48049776;