7-84005396-C-T

Position:

chr7-84005396-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006080.3(SEMA3A):c.1303G>A(p.Val435Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0168 in 1,613,444 control chromosomes in the GnomAD database, including 284 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 15 hom., cov: 32)

Exomes 𝑓: 0.017 ( 269 hom. )

Consequence

SEMA3A
NM_006080.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4O:2

Conservation

PhyloP100: 5.95

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01249221).

BP6

Variant 7-84005396-C-T is Benign according to our data. Variant chr7-84005396-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 39716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-84005396-C-T is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0125 (1904/152192) while in subpopulation NFE AF= 0.0203 (1381/68008). AF 95% confidence interval is 0.0194. There are 15 homozygotes in gnomad4. There are 887 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1904 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SEMA3A	NM_006080.3 linkuse as main transcript	c.1303G>A	p.Val435Ile	missense_variant	11/17	ENST00000265362.9
SEMA3A	XM_005250110.4 linkuse as main transcript	c.1303G>A	p.Val435Ile	missense_variant	14/20
SEMA3A	XM_047419751.1 linkuse as main transcript	c.1303G>A	p.Val435Ile	missense_variant	15/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA3A	ENST00000265362.9 linkuse as main transcript	c.1303G>A	p.Val435Ile	missense_variant	11/17	1	NM_006080.3	P1
SEMA3A	ENST00000436949.5 linkuse as main transcript	c.1303G>A	p.Val435Ile	missense_variant	12/18	5		P1

Frequencies

GnomAD3 genomes

AF:

0.0125

AC:

1905

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00331

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0100

Gnomad ASJ

AF:

0.0113

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00913

Gnomad FIN

AF:

0.0109

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0203

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0136

AC:

3428

AN:

251328

Hom.:

AF XY:

0.0142

AC XY:

1930

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.00301

Gnomad AMR exome

AF:

0.00726

Gnomad ASJ exome

AF:

0.0114

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00853

Gnomad FIN exome

AF:

0.0103

Gnomad NFE exome

AF:

0.0215

Gnomad OTH exome

AF:

0.0135

GnomAD4 exome

AF:

0.0172

AC:

25164

AN:

1461252

Hom.:

269

Cov.:

AF XY:

0.0173

AC XY:

12566

AN XY:

726976

show subpopulations

Gnomad4 AFR exome

AF:

0.00257

Gnomad4 AMR exome

AF:

0.00760

Gnomad4 ASJ exome

AF:

0.0114

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00969

Gnomad4 FIN exome

AF:

0.0117

Gnomad4 NFE exome

AF:

0.0198

Gnomad4 OTH exome

AF:

0.0147

GnomAD4 genome

AF:

0.0125

AC:

1904

AN:

152192

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

887

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.00330

Gnomad4 AMR

AF:

0.00994

Gnomad4 ASJ

AF:

0.0113

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00934

Gnomad4 FIN

AF:

0.0109

Gnomad4 NFE

AF:

0.0203

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0183

Hom.:

Bravo

AF:

0.0117

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0140

AC:

120

ExAC

AF:

0.0138

AC:

1671

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.0218

EpiControl

AF:

0.0207

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2019	This variant is associated with the following publications: (PMID: 22927827, 29255181, 30183078, 28334861, 23643381, 25077900, 21898659, 27884173, 25839327, 24522099, 24963029) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	SEMA3A: BS1, BS2 -

Hypogonadotropic hypogonadism 16 with or without anosmia

Benign:1Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Aug 01, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jul 25, 2022	This variant is present in the Genome Aggregation Database (Highest reported MAF: 2.0% [1382/68016] including 15 total homozygotes; https://gnomad.broadinstitute.org/variant/7-84005396-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:39716). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.95

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.9

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.90

N;N

REVEL

Benign

0.15

Sift

Benign

0.046

D;D

Sift4G

Benign

0.10

T;T

Polyphen

0.11

B;B

Vest4

0.18

MPC

0.39

ClinPred

0.024

GERP RS

5.0

Varity_R

0.35

gMVP

0.45

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