15-47748021-A-G

Variant names:

• chr15-47748021-A-G
• rs4774504
• NM_001358351.3:c.-54-11724A>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.-54-11724A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.85 in 152,222 control chromosomes in the GnomAD database, including 55,775 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 0.85 (55775 hom., cov: 33)
• Consequence: SEMA6D NM_001358351.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.125
• 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 (NFE) allele frequency at 95% confidence interval = 0.927 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.-54-11724A>G		intron	N/A	NP_001345280.1	Q8NFY4-1
	SEMA6D	NM_001358352.2		c.-54-11724A>G		intron	N/A	NP_001345281.1
	SEMA6D	NM_153618.2		c.-54-11724A>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.-54-11724A>G		intron	N/A	ENSP00000446152.3	Q8NFY4-1
	SEMA6D	ENST00000316364.9	TSL:1	c.-54-11724A>G		intron	N/A	ENSP00000324857.5	Q8NFY4-1
	SEMA6D	ENST00000354744.8	TSL:1	c.-54-11724A>G		intron	N/A	ENSP00000346786.4	Q8NFY4-4

Frequencies

GnomAD3 genomes AF: 0.850 AC: 129259 AN: 152104 Hom.: 55763 Cov.: 33

Gnomad AFR AF: 0.736

Gnomad AMI AF: 0.882

Gnomad AMR AF: 0.822

Gnomad ASJ AF: 0.946

Gnomad EAS AF: 0.528

Gnomad SAS AF: 0.917

Gnomad FIN AF: 0.891

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.933

Gnomad OTH AF: 0.849

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

GnomAD4 genome AF: 0.850 AC: 129323 AN: 152222 Hom.: 55775 Cov.: 33 AF XY: 0.847 AC XY: 63079 AN XY: 74434

African (AFR) AF: 0.736 AC: 30549 AN: 41524

American (AMR) AF: 0.822 AC: 12565 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.946 AC: 3284 AN: 3470

East Asian (EAS) AF: 0.529 AC: 2727 AN: 5156

South Asian (SAS) AF: 0.917 AC: 4424 AN: 4826

European-Finnish (FIN) AF: 0.891 AC: 9454 AN: 10608

Middle Eastern (MID) AF: 0.942 AC: 277 AN: 294

European-Non Finnish (NFE) AF: 0.933 AC: 63456 AN: 68032

Other (OTH) AF: 0.846 AC: 1784 AN: 2108

Alfa AF: 0.866 Hom.: 17832

Bravo AF: 0.833

Asia WGS AF: 0.711 AC: 2476 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.74
PhyloP100		-0.13
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: rs4774504; hg19: chr15-48040218;