7-84999660-A-C

Variant names:

• chr7-84999660-A-C
• rs1415076796
• NM_001384900.1:c.2114T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001384900.1(SEMA3D):​c.2114T>G​(p.Leu705Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. L705L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: SEMA3D NM_001384900.1 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.58

Genes affected

SEMA3D (HGNC:10726): (semaphorin 3D) This gene encodes a member of the semaphorin III family of secreted signaling proteins that are involved in axon guidance during neuronal development. The encoded protein contains an N-terminal Sema domain, an immunoglobulin like domain and a C-terminal basic domain. The protein encoded by this gene binds neuropilin and plays an important role in cardiovascular development. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.119800985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3D	NM_001384900.1	c.2114T>G	p.Leu705Arg	missense_variant	Exon 19 of 19	ENST00000284136.11	NP_001371829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA3D	ENST00000284136.11	c.2114T>G	p.Leu705Arg	missense_variant	Exon 19 of 19	5	NM_001384900.1	ENSP00000284136.6
SEMA3D	ENST00000484038.1	n.1240T>G		non_coding_transcript_exon_variant	Exon 10 of 10	1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251402 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461808 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 727212

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33476

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44694

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26130

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39696

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53416

Gnomad4 NFE exome AF: 0.0000387 AC: 43 AN: 1111978

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74320

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.0000147011 AN: 0.0000147011

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

SEMA3D-related disorder Uncertain:1

Jul 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SEMA3D c.2114T>G variant is predicted to result in the amino acid substitution p.Leu705Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.0067	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.096
Sift	Benign	0.54	T
Sift4G	Benign	0.55	T
Polyphen		0.090	B
Vest4		0.27
MutPred		0.47		Gain of MoRF binding (P = 0.0064);
MVP		0.51
MPC		0.28
ClinPred		0.29	T
GERP RS		4.6
Varity_R		0.35
gMVP		0.52
Mutation Taster		=88/12	polymorphism

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: rs1415076796; hg19: chr7-84628976;