7-84999673-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001384900.1(SEMA3D):c.2101A>C(p.Lys701Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 1,613,526 control chromosomes in the GnomAD database, including 81,188 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.32 (7942 hom., cov: 32)
  • Exomes 𝑓: 0.31 (73246 hom.)
• Consequence: SEMA3D NM_001384900.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.55

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=0.003791988).
• BP6: Variant 7-84999673-T-G is Benign according to our data. Variant chr7-84999673-T-G is described in ClinVar as [Benign]. Clinvar id is 3060976.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA3D	NM_001384900.1	c.2101A>C	p.Lys701Gln	missense_variant	19/19	ENST00000284136.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA3D	ENST00000284136.11	c.2101A>C	p.Lys701Gln	missense_variant	19/19	5	NM_001384900.1	P1
SEMA3D	ENST00000484038.1	n.1227A>C		non_coding_transcript_exon_variant	10/10	1

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48715 AN: 151768 Hom.: 7934 Cov.: 32

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.321

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.325

GnomAD3 exomes AF: 0.281 AC: 70729 AN: 251380 Hom.: 10654 AF XY: 0.283 AC XY: 38415 AN XY: 135848

Gnomad AFR exome AF: 0.372

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.281

Gnomad EAS exome AF: 0.278

Gnomad SAS exome AF: 0.206

Gnomad FIN exome AF: 0.244

Gnomad NFE exome AF: 0.327

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.313 AC: 457173 AN: 1461642 Hom.: 73246 Cov.: 36 AF XY: 0.310 AC XY: 225403 AN XY: 727138

Gnomad4 AFR exome AF: 0.370

Gnomad4 AMR exome AF: 0.187

Gnomad4 ASJ exome AF: 0.287

Gnomad4 EAS exome AF: 0.238

Gnomad4 SAS exome AF: 0.208

Gnomad4 FIN exome AF: 0.247

Gnomad4 NFE exome AF: 0.331

Gnomad4 OTH exome AF: 0.306

GnomAD4 genome AF: 0.321 AC: 48743 AN: 151884 Hom.: 7942 Cov.: 32 AF XY: 0.315 AC XY: 23356 AN XY: 74212

Gnomad4 AFR AF: 0.375

Gnomad4 AMR AF: 0.261

Gnomad4 ASJ AF: 0.297

Gnomad4 EAS AF: 0.283

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.240

Gnomad4 NFE AF: 0.327

Gnomad4 OTH AF: 0.323

Alfa AF: 0.323 Hom.: 17254

Bravo AF: 0.324

TwinsUK AF: 0.315 AC: 1169

ALSPAC AF: 0.329 AC: 1268

ESP6500AA AF: 0.373 AC: 1642

ESP6500EA AF: 0.327 AC: 2814

ExAC AF: 0.287 AC: 34869

Asia WGS AF: 0.223 AC: 776 AN: 3478

EpiCase AF: 0.332

EpiControl AF: 0.325

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SEMA3D-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 19, 2022

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	Benign	0.078
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	16
Dann	Benign	0.67
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.10
Sift	Benign	0.66	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.16
ClinPred		0.0016	T
GERP RS		3.8
Varity_R		0.092
gMVP		0.22

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: rs7800072; hg19: chr7-84628989; COSMIC: COSV52394115;