7-84005396-C-G

Variant names:

• chr7-84005396-C-G
• rs147436181
• NM_006080.3:c.1303G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006080.3(SEMA3A):​c.1303G>C​(p.Val435Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V435I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEMA3A NM_006080.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.95
• Publications: 19 publications found

Genes affected

SEMA3A (HGNC:10723): (semaphorin 3A) This gene is a member of the semaphorin family and encodes a protein with an Ig-like C2-type (immunoglobulin-like) domain, a PSI domain and a Sema domain. This secreted protein can function as either a chemorepulsive agent, inhibiting axonal outgrowth, or as a chemoattractive agent, stimulating the growth of apical dendrites. In both cases, the protein is vital for normal neuronal pattern development. Increased expression of this protein is associated with schizophrenia and is seen in a variety of human tumor cell lines. Also, aberrant release of this protein is associated with the progression of Alzheimer's disease. [provided by RefSeq, Jul 2008]

SEMA3A Gene-Disease associations (from GenCC):

• skeletal dysplasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• hypogonadotropic hypogonadism 16 with or without anosmia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3A	NM_006080.3	c.1303G>C	p.Val435Leu	missense_variant	Exon 11 of 17	ENST00000265362.9	NP_006071.1
SEMA3A	XM_005250110.4	c.1303G>C	p.Val435Leu	missense_variant	Exon 14 of 20		XP_005250167.1
SEMA3A	XM_047419751.1	c.1303G>C	p.Val435Leu	missense_variant	Exon 15 of 21		XP_047275707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA3A	ENST00000265362.9	c.1303G>C	p.Val435Leu	missense_variant	Exon 11 of 17	1	NM_006080.3	ENSP00000265362.3
SEMA3A	ENST00000436949.5	c.1303G>C	p.Val435Leu	missense_variant	Exon 12 of 18	5		ENSP00000415260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 66

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.0	.;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;M
PhyloP100		5.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.013	D;D
Sift4G	Benign	0.10	T;T
Vest4		0.72
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.56
gMVP		0.74
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs147436181; hg19: chr7-83634712;