rs199979628

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PS1_ModerateBP4BS2

The NM_006080.3(SEMA3A):c.196C>T(p.Arg66Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000695 in 1,613,752 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 1 hom. )

Consequence

SEMA3A
NM_006080.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3O:1

Conservation

PhyloP100: 2.04

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PS1

Transcript NM_006080.3 (SEMA3A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

BP4

Computational evidence support a benign effect (MetaRNN=0.30604246).

BS2

High AC in GnomAd4 at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SEMA3A	NM_006080.3 linkuse as main transcript	c.196C>T	p.Arg66Trp	missense_variant	2/17	ENST00000265362.9
SEMA3A	XM_005250110.4 linkuse as main transcript	c.196C>T	p.Arg66Trp	missense_variant	5/20
SEMA3A	XM_047419751.1 linkuse as main transcript	c.196C>T	p.Arg66Trp	missense_variant	6/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SEMA3A	ENST00000265362.9 linkuse as main transcript	c.196C>T	p.Arg66Trp	missense_variant	2/17	1	NM_006080.3	P1
SEMA3A	ENST00000436949.5 linkuse as main transcript	c.196C>T	p.Arg66Trp	missense_variant	3/18	5		P1
SEMA3A	ENST00000420047.1 linkuse as main transcript	c.196C>T	p.Arg66Trp	missense_variant	3/5	4

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000525

AC:

132

AN:

251190

Hom.:

AF XY:

0.000545

AC XY:

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000948

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000819

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000726

AC:

1061

AN:

1461498

Hom.:

Cov.:

AF XY:

0.000726

AC XY:

528

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.000800

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000846

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.000394

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000720

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000561

Hom.:

Bravo

AF:

0.000336

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000527

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2021	Identified in patients with Kallmann syndrome, some of whom harbored variants in other genes (Hanchate et al., 2012; Cassatella et al., 2018; Bouilly et al., 2018); Identified in a patient with CHARGE syndrome who was negative for variants in the CHD7 gene; this variant was inherited from a healthy father and was hypothesized to have a modifier role (Schultz et al., 2014); Reported in an individual with unilateral vesicoureteric reflux (Nicolaou et al., 2016), and in one case with sudden unexplained death (Neubauer et al., 2018), however, familial segregation studies were not included in these studies; Published functional studies demonstrate that this variant results in impaired semaphorin-3A secretion (Hanchate et al., 2012; Ufartes et al., 2018); This variant is associated with the following publications: (PMID: 32171629, 33895855, 22927827, 29419413, 29350269, 24728844, 26489027, 29202173, 30098700, 29432577) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 01, 2023	An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects SEMA3A function (PMID: 22927827). ClinVar contains an entry for this variant (Variation ID: 68832). This missense change has been observed in individual(s) with SEMA3A-related conditions (PMID: 22927827, 24728844, 29419413, 30098700). This variant is present in population databases (rs199979628, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 66 of the SEMA3A protein (p.Arg66Trp). -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

SEMA3A-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 26, 2023

The SEMA3A c.196C>T variant is predicted to result in the amino acid substitution p.Arg66Trp. This variant was previously reported in individuals with suspected Kallmann syndrome, congenital hypogonadotropic hypogonadism, or CHARGE syndrome; however, this variant has also been reported in apparently unaffected individuals (Hanchate et al. 2012. PubMed ID: 22927827; Cassatella et al. 2018. PubMed ID: 29419413, Table S2; Schulz et al. 2014. PubMed ID: 24728844). In vitro functional analyses indicated that the p.Arg66Trp variant protein impaired secretion of semaphorin-3A, leading authors to speculate that p.Arg66Trp may contribute to disease in a digenic or oligogenic inheritance pattern (Hanchate et al. 2012. PubMed ID: 22927827; Ufartes et al. 2018. PubMed ID: 29432577). This variant is reported in 0.095% of alleles in individuals of South Asian descent in gnomAD. Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

T;T;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.90

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Pathogenic

3.2

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.2

D;D;D

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.68

MVP

0.54

MPC

0.95

ClinPred

0.19

GERP RS

4.9

Varity_R

0.81

gMVP

0.80

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

Other links and lift over