rs36026860

Positions:

• chr7-84005501-T-C

Variant summary

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

The NM_006080.3(SEMA3A):​c.1198A>G​(p.Ile400Val) variant causes a missense change. The variant allele was found at a frequency of 0.000169 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: SEMA3A NM_006080.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2 O:1
• Conservation: PhyloP100: 4.01

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=0.013648897).
• BS2: High AC in GnomAd4 at 138 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA3A	NM_006080.3	c.1198A>G	p.Ile400Val	missense_variant	11/17	ENST00000265362.9
SEMA3A	XM_005250110.4	c.1198A>G	p.Ile400Val	missense_variant	14/20
SEMA3A	XM_047419751.1	c.1198A>G	p.Ile400Val	missense_variant	15/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA3A	ENST00000265362.9	c.1198A>G	p.Ile400Val	missense_variant	11/17	1	NM_006080.3	P1
SEMA3A	ENST00000436949.5	c.1198A>G	p.Ile400Val	missense_variant	12/18	5		P1

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000243 AC: 61 AN: 251284 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135796

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000924 AC: 135 AN: 1461788 Hom.: 0 Cov.: 31 AF XY: 0.0000811 AC XY: 59 AN XY: 727202

Gnomad4 AFR exome AF: 0.00296

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000906 AC: 138 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000967 AC XY: 72 AN XY: 74460

Gnomad4 AFR AF: 0.00286

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000144 Hom.: 0

Bravo AF: 0.00100

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000362 AC: 44

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 02, 2023	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

Hypogonadotropic hypogonadism 16 with or without anosmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

SEMA3A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 03, 2021

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	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.048
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.44	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.75	N;N
REVEL	Benign	0.11
Sift	Benign	0.43	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.21	B;B
Vest4		0.66
MVP		0.45
MPC		0.23
ClinPred		0.016	T
GERP RS		5.0
Varity_R		0.15
gMVP		0.21

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: rs36026860; hg19: chr7-83634817;