7-85006867-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001384900.1(SEMA3D):c.1843C>A(p.Pro615Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,610,048 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (18 hom.)
• Consequence: SEMA3D NM_001384900.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.81

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038127005).
• BP6: Variant 7-85006867-G-T is Benign according to our data. Variant chr7-85006867-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 782021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA3D	NM_001384900.1	c.1843C>A	p.Pro615Thr	missense_variant	18/19	ENST00000284136.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA3D	ENST00000284136.11	c.1843C>A	p.Pro615Thr	missense_variant	18/19	5	NM_001384900.1	P1
SEMA3D	ENST00000484038.1	n.969C>A		non_coding_transcript_exon_variant	9/10	1

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 384 AN: 151820 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000991

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00513

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00350

Gnomad OTH AF: 0.00432

GnomAD3 exomes AF: 0.00238 AC: 595 AN: 249640 Hom.: 1 AF XY: 0.00221 AC XY: 298 AN XY: 135048

Gnomad AFR exome AF: 0.000932

Gnomad AMR exome AF: 0.00320

Gnomad ASJ exome AF: 0.00378

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00358

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.00403 AC: 5872 AN: 1458110 Hom.: 18 Cov.: 29 AF XY: 0.00388 AC XY: 2817 AN XY: 725510

Gnomad4 AFR exome AF: 0.000842

Gnomad4 AMR exome AF: 0.00382

Gnomad4 ASJ exome AF: 0.00327

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000525

Gnomad4 NFE exome AF: 0.00482

Gnomad4 OTH exome AF: 0.00341

GnomAD4 genome AF: 0.00253 AC: 384 AN: 151938 Hom.: 2 Cov.: 32 AF XY: 0.00263 AC XY: 195 AN XY: 74258

Gnomad4 AFR AF: 0.000988

Gnomad4 AMR AF: 0.00512

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00350

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00350 Hom.: 3

Bravo AF: 0.00286

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00225 AC: 273

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	SEMA3D: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

SEMA3D-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 19, 2021

This variant is classified as likely 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	Uncertain	0.53
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.94	P
Vest4		0.75
MVP		0.93
MPC		0.66
ClinPred		0.053	T
GERP RS		6.0
Varity_R		0.62
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs117730916; hg19: chr7-84636183;