Variant 15-47761185-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001358351.3(SEMA6D):c.310G>C(p.Asp104His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SEMA6D
NM_001358351.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEMA6D	NM_001358351.3 linkuse as main transcript	c.310G>C	p.Asp104His	missense_variant	5/19	ENST00000536845.7	NP_001345280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEMA6D	ENST00000536845.7 linkuse as main transcript	c.310G>C	p.Asp104His	missense_variant	5/19	2	NM_001358351.3	ENSP00000446152.3		Q8NFY4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250410

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135300

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461490

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.310G>C (p.D104H) alteration is located in exon 5 (coding exon 4) of the SEMA6D gene. This alteration results from a G to C substitution at nucleotide position 310, causing the aspartic acid (D) at amino acid position 104 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.043

.;T;T;.;.;.;T;.;.;.;.

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

.;D;.;.;D;D;D;D;D;D;D

M_CAP

Benign

0.024

MetaRNN

Pathogenic

0.76

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.8

L;.;L;L;L;L;L;L;L;L;.

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.2

D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

D;D;D;D;T;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;T;T;T;D;D;D;D;D

Polyphen

1.0

D;.;D;.;.;.;D;D;D;D;.

Vest4

0.80

MutPred

0.56

Gain of MoRF binding (P = 0.0481);Gain of MoRF binding (P = 0.0481);Gain of MoRF binding (P = 0.0481);Gain of MoRF binding (P = 0.0481);Gain of MoRF binding (P = 0.0481);Gain of MoRF binding (P = 0.0481);Gain of MoRF binding (P = 0.0481);Gain of MoRF binding (P = 0.0481);Gain of MoRF binding (P = 0.0481);Gain of MoRF binding (P = 0.0481);Gain of MoRF binding (P = 0.0481);

MVP

0.51

MPC

1.8

ClinPred

0.99

GERP RS

6.0

Varity_R

0.94

gMVP

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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