rs532598

Positions:

• chr15-47765874-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001358351.3(SEMA6D):​c.1433G>A​(p.Ser478Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 1,510,420 control chromosomes in the GnomAD database, including 102,674 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.43 (15188 hom., cov: 33)
  • Exomes 𝑓: 0.35 (87486 hom.)
• Consequence: SEMA6D NM_001358351.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.310

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.88815E-6).
• BP6: Variant 15-47765874-G-A is Benign according to our data. Variant chr15-47765874-G-A is described in ClinVar as [Benign]. Clinvar id is 3060165.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEMA6D	NM_001358351.3	c.1433G>A	p.Ser478Asn	missense_variant	14/19	ENST00000536845.7	NP_001345280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEMA6D	ENST00000536845.7	c.1433G>A	p.Ser478Asn	missense_variant	14/19	2	NM_001358351.3	ENSP00000446152.3

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65833 AN: 151910 Hom.: 15183 Cov.: 33

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.591

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.414

GnomAD3 exomes AF: 0.398 AC: 72000 AN: 180842 Hom.: 15172 AF XY: 0.389 AC XY: 37029 AN XY: 95152

Gnomad AFR exome AF: 0.584

Gnomad AMR exome AF: 0.396

Gnomad ASJ exome AF: 0.390

Gnomad EAS exome AF: 0.588

Gnomad SAS exome AF: 0.343

Gnomad FIN exome AF: 0.433

Gnomad NFE exome AF: 0.336

Gnomad OTH exome AF: 0.385

GnomAD4 exome AF: 0.352 AC: 478237 AN: 1358392 Hom.: 87486 Cov.: 34 AF XY: 0.352 AC XY: 233888 AN XY: 664896

Gnomad4 AFR exome AF: 0.591

Gnomad4 AMR exome AF: 0.404

Gnomad4 ASJ exome AF: 0.384

Gnomad4 EAS exome AF: 0.596

Gnomad4 SAS exome AF: 0.341

Gnomad4 FIN exome AF: 0.431

Gnomad4 NFE exome AF: 0.330

Gnomad4 OTH exome AF: 0.374

GnomAD4 genome AF: 0.433 AC: 65879 AN: 152028 Hom.: 15188 Cov.: 33 AF XY: 0.438 AC XY: 32539 AN XY: 74284

Gnomad4 AFR AF: 0.581

Gnomad4 AMR AF: 0.413

Gnomad4 ASJ AF: 0.386

Gnomad4 EAS AF: 0.591

Gnomad4 SAS AF: 0.350

Gnomad4 FIN AF: 0.443

Gnomad4 NFE AF: 0.346

Gnomad4 OTH AF: 0.415

Alfa AF: 0.363 Hom.: 24362

Bravo AF: 0.436

TwinsUK AF: 0.333 AC: 1233

ALSPAC AF: 0.342 AC: 1317

ESP6500AA AF: 0.587 AC: 2581

ESP6500EA AF: 0.334 AC: 2874

ExAC AF: 0.384 AC: 45777

Asia WGS AF: 0.468 AC: 1626 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

SEMA6D-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.6
DANN	Benign	0.68
DEOGEN2	Benign	0.041	.;T;.;.;T;.;.;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.31	.;.;.;T;T;T;T;T
MetaRNN	Benign	0.0000089	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.92	L;L;L;L;L;L;L;L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.89	N;N;N;N;N;N;N;N
REVEL	Benign	0.032
Sift	Benign	0.39	T;T;T;T;T;T;T;T
Sift4G	Benign	0.98	T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;.;B;B;B;B
Vest4		0.050
MPC		0.072
ClinPred		0.0010	T
GERP RS		-1.9
Varity_R		0.052
gMVP		0.13

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

Publications

LitVar

Other links and lift over

dbSNP: rs532598; hg19: chr15-48058071; COSMIC: COSV105881756; COSMIC: COSV105881756;