chr7-84005396-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

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:5O:2

Conservation

PhyloP100: 5.95

Publications

19 publications found

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 Gene-Disease associations (from GenCC):

skeletal dysplasia
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
hypogonadotropic hypogonadism 16 with or without anosmia
Inheritance: AD, SD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, 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

SEMA3A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 39716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006080.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA3A	NM_006080.3	MANE Select	c.1303G>A	p.Val435Ile	missense	Exon 11 of 17	NP_006071.1	Q14563

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SEMA3A	ENST00000265362.9	TSL:1 MANE Select	c.1303G>A	p.Val435Ile	missense	Exon 11 of 17	ENSP00000265362.3	Q14563
SEMA3A	ENST00000436949.5	TSL:5	c.1303G>A	p.Val435Ile	missense	Exon 12 of 18	ENSP00000415260.1	Q14563
SEMA3A	ENST00000864988.1		c.1303G>A	p.Val435Ile	missense	Exon 16 of 22	ENSP00000535047.1

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

GnomAD2 exomes

AF:

0.0136

AC:

3428

AN:

251328

AF XY:

0.0142

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 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

African (AFR)

AF:

0.00257

AC:

AN:

33478

American (AMR)

AF:

0.00760

AC:

340

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0114

AC:

298

AN:

26120

East Asian (EAS)

AF:

0.000101

AC:

AN:

39676

South Asian (SAS)

AF:

0.00969

AC:

836

AN:

86250

European-Finnish (FIN)

AF:

0.0117

AC:

627

AN:

53390

Middle Eastern (MID)

AF:

0.0182

AC:

105

AN:

5766

European-Non Finnish (NFE)

AF:

0.0198

AC:

21980

AN:

1111486

Other (OTH)

AF:

0.0147

AC:

888

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

1198

2395

3593

4790

5988

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

782

1564

2346

3128

3910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0125

AC:

1904

AN:

152192

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

887

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.00330

AC:

137

AN:

41536

American (AMR)

AF:

0.00994

AC:

152

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

AN:

3464

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.00934

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0109

AC:

115

AN:

10594

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0203

AC:

1381

AN:

68008

Other (OTH)

AF:

0.0123

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

197

295

394

492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0173

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Hypogonadotropic hypogonadism 16 with or without anosmia (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.9

PhyloP100

5.9

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.90

REVEL

Benign

0.15

Sift

Benign

0.046

Sift4G

Benign

0.10

Polyphen

0.11

Vest4

0.18

MPC

0.39

ClinPred

0.024

GERP RS

5.0

Varity_R

0.35

gMVP

0.45

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over