rs3743279

chr15-47764022-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001358351.3(SEMA6D):c.920A>G(p.Asn307Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0195 in 1,613,834 control chromosomes in the GnomAD database, including 2,915 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.074 (1250 hom., cov: 33)
  • Exomes 𝑓: 0.014 (1665 hom.)
• Consequence: SEMA6D NM_001358351.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.54

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015435815).
• BP6: Variant 15-47764022-A-G is Benign according to our data. Variant chr15-47764022-A-G is described in ClinVar as [Benign]. Clinvar id is 3057033.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA6D	NM_001358351.3	c.920A>G	p.Asn307Ser	missense_variant	10/19	ENST00000536845.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA6D	ENST00000536845.7	c.920A>G	p.Asn307Ser	missense_variant	10/19	2	NM_001358351.3	P4

Frequencies

GnomAD3 genomes AF: 0.0735 AC: 11177 AN: 152060 Hom.: 1241 Cov.: 33

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0714

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0440

GnomAD3 exomes AF: 0.0343 AC: 8590 AN: 250584 Hom.: 728 AF XY: 0.0330 AC XY: 4466 AN XY: 135408

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.00859

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0707

Gnomad SAS exome AF: 0.0937

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000611

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.0139 AC: 20276 AN: 1461656 Hom.: 1665 Cov.: 33 AF XY: 0.0150 AC XY: 10935 AN XY: 727136

Gnomad4 AFR exome AF: 0.248

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0519

Gnomad4 SAS exome AF: 0.0868

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000288

Gnomad4 OTH exome AF: 0.0265

GnomAD4 genome AF: 0.0738 AC: 11232 AN: 152178 Hom.: 1250 Cov.: 33 AF XY: 0.0725 AC XY: 5394 AN XY: 74376

Gnomad4 AFR AF: 0.238

Gnomad4 AMR AF: 0.0215

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0716

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.0482

Alfa AF: 0.0152 Hom.: 487

Bravo AF: 0.0799

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.227 AC: 999

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.0396 AC: 4809

Asia WGS AF: 0.114 AC: 396 AN: 3476

EpiCase AF: 0.000763

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SEMA6D-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 14, 2020

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	0.076
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.0015	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L;L;L;L;L;L;L;L;L
MutationTaster	Benign	0.0011	P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D;D;D;D
Sift	Benign	0.073	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.066	T;T;T;T;T;T;T;T;T
Polyphen		0.98	D;B;.;.;.;B;D;D;D
Vest4		0.13
MPC		0.52
ClinPred		0.067	T
GERP RS		1.1
Varity_R		0.33
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3743279; hg19: chr15-48056219; COSMIC: COSV60376575; COSMIC: COSV60376575;