NM_001384900.1:c.2170A>G

Variant names:

• chr7-84999604-T-C
• rs1789598126
• NM_001384900.1:c.2170A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001384900.1(SEMA3D):​c.2170A>G​(p.Asn724Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEMA3D NM_001384900.1 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.75
• Publications: 0 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 2 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity SEM3D_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13502946).

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.2170A>G	p.Asn724Asp	missense	Exon 19 of 19	NP_001371829.1	O95025
	SEMA3D	NM_001384901.1		c.2170A>G	p.Asn724Asp	missense	Exon 20 of 20	NP_001371830.1	O95025
	SEMA3D	NM_001384902.1		c.2170A>G	p.Asn724Asp	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.2170A>G	p.Asn724Asp	missense	Exon 19 of 19	ENSP00000284136.6	O95025
	SEMA3D	ENST00000484038.1	TSL:1	n.1296A>G		non_coding_transcript_exon	Exon 10 of 10
	SEMA3D	ENST00000916323.1		c.2170A>G	p.Asn724Asp	missense	Exon 18 of 18	ENSP00000586382.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	SEMA3D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.030
Sift	Benign	0.19	T
Sift4G	Benign	0.35	T
Polyphen		0.057	B
Vest4		0.090
MutPred		0.38		Gain of sheet (P = 0.0125)
MVP		0.59
MPC		0.18
ClinPred		0.30	T
GERP RS		5.7
Varity_R		0.21
gMVP		0.20
Mutation Taster		=94/6	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: rs1789598126; hg19: chr7-84628920;