dbSNP rs141893504: SEMA3D:p.His424Gln (chr7-85022533-G-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0042 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 24 hom. )

Consequence

SEMA3D
NM_001384900.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:3

Conservation

PhyloP100: 1.65

Publications

15 publications found

Variant links:

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

SEMA3D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 523626.

BS2

High AC in GnomAd4 at 639 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SEMA3D	NM_001384900.1	MANE Select	c.1272C>A	p.His424Gln	missense	Exon 13 of 19	NP_001371829.1	O95025
SEMA3D	NM_001384901.1		c.1272C>A	p.His424Gln	missense	Exon 14 of 20	NP_001371830.1	O95025
SEMA3D	NM_001384902.1		c.1272C>A	p.His424Gln	missense	Exon 15 of 21	NP_001371831.1	O95025

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SEMA3D	ENST00000284136.11	TSL:5 MANE Select	c.1272C>A	p.His424Gln	missense	Exon 13 of 19	ENSP00000284136.6	O95025
SEMA3D	ENST00000484038.1	TSL:1	n.398C>A		non_coding_transcript_exon	Exon 4 of 10
SEMA3D	ENST00000916323.1		c.1272C>A	p.His424Gln	missense	Exon 12 of 18	ENSP00000586382.1

Frequencies

GnomAD3 genomes

AF:

0.00421

AC:

639

AN:

151786

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00400

AC:

1004

AN:

250794

AF XY:

0.00413

show subpopulations

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 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.:

Cov.:

AF XY:

0.00495

AC XY:

3595

AN XY:

726608

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

33390

American (AMR)

AF:

0.00289

AC:

129

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.0139

AC:

362

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.000302

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00249

AC:

133

AN:

53416

Middle Eastern (MID)

AF:

0.00782

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00569

AC:

6327

AN:

1111008

Other (OTH)

AF:

0.00638

AC:

385

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

369

739

1108

1478

1847

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

232

464

696

928

1160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00421

AC:

639

AN:

151904

Hom.:

Cov.:

AF XY:

0.00381

AC XY:

283

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.000915

AC:

AN:

41508

American (AMR)

AF:

0.00401

AC:

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00283

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00642

AC:

436

AN:

67860

Other (OTH)

AF:

0.00713

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

101

134

168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00544

Hom.:

Bravo

AF:

0.00414

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00523

AC:

ExAC

AF:

0.00371

AC:

451

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00764

EpiControl

AF:

0.00670

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Aganglionic megacolon (2)

not provided (2)

SEMA3D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Uncertain

0.12

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.63

MutationAssessor

Pathogenic

3.8

PhyloP100

1.6

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-7.8

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MutPred

0.90

Loss of catalytic residue at S425 (P = 0.1052)

MVP

0.60

MPC

0.65

ClinPred

0.11

GERP RS

0.088

Varity_R

0.93

gMVP

0.85

Mutation Taster

=30/70

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over