7-83961537-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006080.3(SEMA3A):c.2150C>T(p.Thr717Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00052 in 1,614,078 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T717M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (4 hom.)
• Consequence: SEMA3A NM_006080.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:3
• Conservation: PhyloP100: 5.12

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008771241).
• BS2: High AC in GnomAd at 114 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA3A	NM_006080.3	c.2150C>T	p.Thr717Ile	missense_variant	17/17	ENST00000265362.9
SEMA3A	XM_005250110.4	c.2150C>T	p.Thr717Ile	missense_variant	20/20
SEMA3A	XM_047419751.1	c.2150C>T	p.Thr717Ile	missense_variant	21/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA3A	ENST00000265362.9	c.2150C>T	p.Thr717Ile	missense_variant	17/17	1	NM_006080.3	P1
SEMA3A	ENST00000436949.5	c.2150C>T	p.Thr717Ile	missense_variant	18/18	5		P1

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00116 AC: 292 AN: 251298 Hom.: 3 AF XY: 0.00117 AC XY: 159 AN XY: 135804

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.000497 AC: 726 AN: 1461814 Hom.: 4 Cov.: 33 AF XY: 0.000513 AC XY: 373 AN XY: 727214

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.0166

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74456

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00103 Hom.: 2

Bravo AF: 0.000661

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000997 AC: 121

EpiCase AF: 0.000436

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2019	This variant is associated with the following publications: (PMID: 29255181, 25636053) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Delayed puberty Pathogenic:1

Likely pathogenic, criteria provided, single submitter

case-control

Chan Lab, Boston Children's Hospital

Nov 01, 2014

- -

SEMA3A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2022

This variant is classified as likely 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	Pathogenic	0.71
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0088	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.16
Sift	Benign	0.21	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.95	P;P
Vest4		0.45
MVP		0.31
MPC		0.45
ClinPred		0.75	D
GERP RS		5.8
Varity_R		0.19
gMVP		0.36

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

Other links and lift over

dbSNP: rs138952094; hg19: chr7-83590853; COSMIC: COSV54893456;