SEMA6D

protein-coding

semaphorin 6D, the group of Semaphorins

Gene summary

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]

MANE transcript

NM_001358351.3

Inheritance

ClinVar variants

U:128B:22

Top phenotype

SEMA6D-related disorder

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr15:47,184,101-47,774,228

External References & Databases

Ensembl (ENSG00000137872)

Transcript & Mutation Effects

hg38 • Region Span ~590.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SEMA6D variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 125

SEMA6D-related disorderTotal: 20

not providedTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001358351.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	13 clinvar	1 clinvar	15
missense			125 clinvar	5 clinvar	3 clinvar	133
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	128	18	4	150

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 76 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001358351.3	RefSeq	NP_001345280.1	18	MANE Select
ENST00000536845.7	Ensembl	ENSP00000446152.3	18	MANE Select
NM_001198999.2	RefSeq	NP_001185928.1	16	Standard
NM_001358352.2	RefSeq	NP_001345281.1	18	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Axon guidance - Homo sapiens (human)
Developmental Biology
Other semaphorin interactions
Semaphorin interactions
Axon guidance

Biological Process

neural crest cell migration
positive regulation of smooth muscle cell migration
negative regulation of smooth muscle cell migration
ventricular system development
positive regulation of cell migration

Molecular Function

semaphorin receptor binding
neuropilin binding
chemorepellent activity

Cellular Component

extracellular space
Golgi apparatus
plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000316364
Coding exons: 18
Length: 590123
Individuals with no LoFs: 125702
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 125716
p: 0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.08	528	603	0.876	0.0000334	7038
Missense (PolyPhen)		174	258.43	0.6733		2972
Synonymous	0.146	223	226	0.988	0.0000133	2107
Loss of Function	5.26	9	48.6	0.185	0.00000273	586

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.00016	0.00016	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Shows growth cone collapsing activity on dorsal root ganglion (DRG) neurons in vitro. May be a stop signal for the DRG neurons in their target areas, and possibly also for other neurons. May also be involved in the maintenance and remodeling of neuronal connections.;

Recessive Scores

pRec: 0.158

Intolerance Scores

LoFtool: 0.289
RVIS EVS: -0.73
RVIS percentile EVS: 14.24

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.134

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium