rs141893504

Positions:

• chr7-85022533-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001384900.1(SEMA3D):​c.1272C>A​(p.His424Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00501 in 1,612,420 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (24 hom.)
• Consequence: SEMA3D NM_001384900.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:3
• Conservation: PhyloP100: 1.65

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10156855).
• BP6: Variant 7-85022533-G-T is Benign according to our data. Variant chr7-85022533-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 523626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEMA3D	NM_001384900.1	c.1272C>A	p.His424Gln	missense_variant	13/19	ENST00000284136.11	NP_001371829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEMA3D	ENST00000284136.11	c.1272C>A	p.His424Gln	missense_variant	13/19	5	NM_001384900.1	ENSP00000284136	P1
SEMA3D	ENST00000484038.1	n.398C>A		non_coding_transcript_exon_variant	4/10	1

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 639 AN: 151786 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000918

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00401

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00642

Gnomad OTH AF: 0.00720

GnomAD3 exomes AF: 0.00400 AC: 1004 AN: 250794 Hom.: 1 AF XY: 0.00413 AC XY: 560 AN XY: 135540

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.00592

Gnomad OTH exome AF: 0.00573

GnomAD4 exome AF: 0.00510 AC: 7444 AN: 1460516 Hom.: 24 Cov.: 31 AF XY: 0.00495 AC XY: 3595 AN XY: 726608

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00289

Gnomad4 ASJ exome AF: 0.0139

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.00249

Gnomad4 NFE exome AF: 0.00569

Gnomad4 OTH exome AF: 0.00638

GnomAD4 genome AF: 0.00421 AC: 639 AN: 151904 Hom.: 3 Cov.: 32 AF XY: 0.00381 AC XY: 283 AN XY: 74238

Gnomad4 AFR AF: 0.000915

Gnomad4 AMR AF: 0.00401

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.00642

Gnomad4 OTH AF: 0.00713

Alfa AF: 0.00619 Hom.: 2

Bravo AF: 0.00414

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00371 AC: 451

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.00764

EpiControl AF: 0.00670

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aganglionic megacolon Pathogenic:1 Uncertain:1

Likely pathogenic, flagged submission	research	Human Genomics Unit, Institute for molecular medicine Finland (FIMM)	-	- -
Uncertain significance, flagged submission	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Nov 20, 2017	This variant was identified in a patient with Hirschsprung disease and a positive familial history. The patient harbours also a variant in the RET gene, which is a risk factor for this disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	SEMA3D: BS1, BS2 -

SEMA3D-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.90		Loss of catalytic residue at S425 (P = 0.1052);
MVP		0.60
MPC		0.65
ClinPred		0.11	T
GERP RS		0.088
Varity_R		0.93
gMVP		0.85

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: rs141893504; hg19: chr7-84651849;