chr7-84999660-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. 15/22 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. 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 criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.58
• Publications: 1 publications found

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]

SEMA3D Gene-Disease associations (from GenCC):

• skeletal dysplasia

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384900.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA3D	NM_001384900.1	MANE Select	c.2114T>G	p.Leu705Arg	missense	Exon 19 of 19	NP_001371829.1	O95025
	SEMA3D	NM_001384901.1		c.2114T>G	p.Leu705Arg	missense	Exon 20 of 20	NP_001371830.1	O95025
	SEMA3D	NM_001384902.1		c.2114T>G	p.Leu705Arg	missense	Exon 21 of 21	NP_001371831.1	O95025

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA3D	ENST00000284136.11	TSL:5 MANE Select	c.2114T>G	p.Leu705Arg	missense	Exon 19 of 19	ENSP00000284136.6	O95025
	SEMA3D	ENST00000484038.1	TSL:1	n.1240T>G		non_coding_transcript_exon	Exon 10 of 10
	SEMA3D	ENST00000916323.1		c.2114T>G	p.Leu705Arg	missense	Exon 18 of 18	ENSP00000586382.1

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

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1111978

Other (OTH) 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

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	1	-	SEMA3D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.6
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

Other links and lift over

dbSNP: rs1415076796; hg19: chr7-84628976;