7-83367599-G-A

Variant summary

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

The NM_012431.3(SEMA3E):c.2315C>T(p.Thr772Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T772T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SEMA3E NM_012431.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27

Genes affected

SEMA3E (HGNC:10727): (semaphorin 3E) Semaphorins are a large family of conserved secreted and membrane associated proteins which possess a semaphorin (Sema) domain and a PSI domain (found in plexins, semaphorins and integrins) in the N-terminal extracellular portion. Based on sequence and structural similarities, semaphorins are put into eight classes: invertebrates contain classes 1 and 2, viruses have class V, and vertebrates contain classes 3-7. Semaphorins serve as axon guidance ligands via multimeric receptor complexes, some (if not all) containing plexin proteins. This gene encodes a class 4 semaphorin. This gene encodes a class 3 semaphorin. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06789139).
• BS2: High AC in GnomAdExome at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA3E	NM_012431.3	c.2315C>T	p.Thr772Met	missense_variant	17/17	ENST00000643230.2
SEMA3E	NM_001178129.2	c.2135C>T	p.Thr712Met	missense_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA3E	ENST00000643230.2	c.2315C>T	p.Thr772Met	missense_variant	17/17		NM_012431.3	P1
SEMA3E	ENST00000643441.1	n.2300C>T		non_coding_transcript_exon_variant	17/17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000596 AC: 15 AN: 251492 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135922

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461818 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

CHARGE syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 08, 2023

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 772 of the SEMA3E protein (p.Thr772Met). This variant is present in population databases (rs766002060, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SEMA3E-related conditions. 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 tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.046	N
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.068	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.0	N;.;N
REVEL	Benign	0.066
Sift	Uncertain	0.014	D;.;D
Sift4G	Uncertain	0.0090	D;.;D
Polyphen		0.92	P;P;.
Vest4		0.091
MutPred		0.18		Loss of phosphorylation at T772 (P = 0.021);Loss of phosphorylation at T772 (P = 0.021);.;
MVP		0.49
MPC		0.31
ClinPred		0.60	D
GERP RS		2.7
Varity_R		0.048
gMVP		0.32

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: rs766002060; hg19: chr7-82996915; COSMIC: COSV57113635; COSMIC: COSV57113635;