Variant chr15-47763920-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001358351.3(SEMA6D):c.818A>G(p.His273Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SEMA6D
NM_001358351.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEMA6D	NM_001358351.3 link	c.818A>G	p.His273Arg	missense_variant	10/19	ENST00000536845.7	NP_001345280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEMA6D	ENST00000536845.7 link	c.818A>G	p.His273Arg	missense_variant	10/19	2	NM_001358351.3	ENSP00000446152.3		Q8NFY4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461664

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

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

Jul 05, 2023

The c.818A>G (p.H273R) alteration is located in exon 10 (coding exon 9) of the SEMA6D gene. This alteration results from a A to G substitution at nucleotide position 818, causing the histidine (H) at amino acid position 273 to be replaced by an arginine (R). 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

0.94

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

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

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.0087

MetaRNN

Uncertain

0.60

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.79

N;N;N;N;N;N;N;N;N

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-3.3

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

REVEL

Uncertain

0.44

Sift

Benign

0.41

T;T;T;T;T;T;T;T;T

Sift4G

Uncertain

0.041

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

Polyphen

0.98

D;P;.;.;.;P;D;D;D

Vest4

0.83

MutPred

0.44

Gain of MoRF binding (P = 0.02);Gain of MoRF binding (P = 0.02);Gain of MoRF binding (P = 0.02);Gain of MoRF binding (P = 0.02);Gain of MoRF binding (P = 0.02);Gain of MoRF binding (P = 0.02);Gain of MoRF binding (P = 0.02);Gain of MoRF binding (P = 0.02);Gain of MoRF binding (P = 0.02);

MVP

0.34

MPC

1.8

ClinPred

0.89

GERP RS

5.9

Varity_R

0.52

gMVP

0.55

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over