chr15-47749949-A-G

Variant names:

• chr15-47749949-A-G
• rs76739
• NM_001358351.3:c.-54-9796A>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.-54-9796A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 152,064 control chromosomes in the GnomAD database, including 8,646 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 0.30 (8646 hom., cov: 31)
• Consequence: SEMA6D NM_001358351.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.258
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.412 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.-54-9796A>G		intron	N/A	NP_001345280.1	Q8NFY4-1
	SEMA6D	NM_001358352.2		c.-54-9796A>G		intron	N/A	NP_001345281.1
	SEMA6D	NM_153618.2		c.-54-9796A>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.-54-9796A>G		intron	N/A	ENSP00000446152.3	Q8NFY4-1
	SEMA6D	ENST00000316364.9	TSL:1	c.-54-9796A>G		intron	N/A	ENSP00000324857.5	Q8NFY4-1
	SEMA6D	ENST00000354744.8	TSL:1	c.-54-9796A>G		intron	N/A	ENSP00000346786.4	Q8NFY4-4

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46245 AN: 151944 Hom.: 8646 Cov.: 31

Gnomad AFR AF: 0.0803

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.403

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.416

Gnomad OTH AF: 0.331

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

GnomAD4 genome AF: 0.304 AC: 46239 AN: 152064 Hom.: 8646 Cov.: 31 AF XY: 0.299 AC XY: 22218 AN XY: 74316

African (AFR) AF: 0.0800 AC: 3323 AN: 41530

American (AMR) AF: 0.370 AC: 5647 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 1396 AN: 3468

East Asian (EAS) AF: 0.279 AC: 1439 AN: 5162

South Asian (SAS) AF: 0.297 AC: 1427 AN: 4802

European-Finnish (FIN) AF: 0.333 AC: 3520 AN: 10574

Middle Eastern (MID) AF: 0.418 AC: 122 AN: 292

European-Non Finnish (NFE) AF: 0.416 AC: 28240 AN: 67942

Other (OTH) AF: 0.326 AC: 688 AN: 2108

Alfa AF: 0.387 Hom.: 39123

Bravo AF: 0.300

Asia WGS AF: 0.249 AC: 864 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.95
DANN	Benign	0.46
PhyloP100		-0.26
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: rs76739; hg19: chr15-48042146;