dbSNP rs318240753: SEMA3A:p.Arg733Leu (chr7-83961489-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM5BP4_ModerateBS2

The NM_006080.3(SEMA3A):c.2198G>T(p.Arg733Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R733C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SEMA3A
NM_006080.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.69

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 -4 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-83961489-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.20326251).

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3A	NM_006080.3 link	c.2198G>T	p.Arg733Leu	missense_variant	Exon 17 of 17	ENST00000265362.9	NP_006071.1	Q14563
SEMA3A	XM_005250110.4 link	c.2198G>T	p.Arg733Leu	missense_variant	Exon 20 of 20		XP_005250167.1	Q14563
SEMA3A	XM_047419751.1 link	c.2198G>T	p.Arg733Leu	missense_variant	Exon 21 of 21		XP_047275707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA3A	ENST00000265362.9 link	c.2198G>T	p.Arg733Leu	missense_variant	Exon 17 of 17	1	NM_006080.3	ENSP00000265362.3		Q14563
SEMA3A	ENST00000436949.5 link	c.2198G>T	p.Arg733Leu	missense_variant	Exon 18 of 18	5		ENSP00000415260.1		Q14563

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461792

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

T;T

Eigen

Benign

0.11

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

.;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

M;M

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.15

Sift

Benign

0.20

T;T

Sift4G

Benign

0.22

T;T

Polyphen

0.28

B;B

Vest4

0.34

MutPred

0.41

Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);

MVP

0.22

MPC

0.72

ClinPred

0.76

GERP RS

6.1

Varity_R

0.28

gMVP

0.37

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over