NM_012431.3:c.1637G>T

Variant names:

• chr7-83392585-C-A
• rs769248913
• NM_012431.3:c.1637G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012431.3(SEMA3E):​c.1637G>T​(p.Arg546Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: SEMA3E NM_012431.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.14

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3E	NM_012431.3	c.1637G>T	p.Arg546Leu	missense_variant	Exon 14 of 17	ENST00000643230.2	NP_036563.1
SEMA3E	NM_001178129.2	c.1457G>T	p.Arg486Leu	missense_variant	Exon 14 of 17		NP_001171600.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA3E	ENST00000643230.2	c.1637G>T	p.Arg546Leu	missense_variant	Exon 14 of 17		NM_012431.3	ENSP00000496491.1
SEMA3E	ENST00000642232.1	c.1637G>T	p.Arg546Leu	missense_variant	Exon 14 of 17			ENSP00000494064.1
SEMA3E	ENST00000643441.1	n.1622G>T		non_coding_transcript_exon_variant	Exon 14 of 17

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151770 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151874 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74200

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;D;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	M;M;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.5	D;.;D;.
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D;.;D;.
Sift4G	Uncertain	0.0040	D;.;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.91
MutPred		0.57		Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);.;Gain of sheet (P = 0.0085);
MVP		0.72
MPC		0.62
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.69
gMVP		0.69

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: rs769248913; hg19: chr7-83021901;