rs61729806

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_001353214.3(DYM):c.421A>G(p.Ser141Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,608,516 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S141N) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.011 ( 32 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 25 hom. )

Consequence

DYM
NM_001353214.3 missense, splice_region

Scores

Splicing: ADA: 0.0007723

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.617

Publications

5 publications found

Variant links:

Genes affected

DYM (HGNC:21317): (dymeclin) This gene encodes a protein which regulates Golgi-associated secretory pathways that are essential to endochondral bone formation during early development. This gene is also believed to play a role in early brain development. This gene is widely expressed in embryos and is particularly abundant in chodrocytes and brain tissues. It encodes a peripheral membrane protein which shuttles between the cytosol and Golgi complex. Mutations in this gene are associated with two types of recessive osteochondrodysplasia: Dyggve-Melchior-Clausen (DMC) dysplasia and Smith-McCort (SMC) dysplasia. [provided by RefSeq, Jun 2017]

DYM Gene-Disease associations (from GenCC):

Dyggve-Melchior-Clausen disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
Smith-McCort dysplasia 1
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Smith-McCort dysplasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DYM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-49363233-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 191094.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034909546).

BP6

Variant 18-49378567-T-C is Benign according to our data. Variant chr18-49378567-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 326903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0114 (1740/152324) while in subpopulation AFR AF = 0.0396 (1644/41564). AF 95% confidence interval is 0.038. There are 32 homozygotes in GnomAd4. There are 831 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYM	NM_001353214.3 link	c.421A>G	p.Ser141Gly	missense_variant, splice_region_variant	Exon 5 of 18	ENST00000675505.1	NP_001340143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYM	ENST00000675505.1 link	c.421A>G	p.Ser141Gly	missense_variant, splice_region_variant	Exon 5 of 18		NM_001353214.3	ENSP00000501694.1

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1729

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0394

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00318

AC:

797

AN:

250850

AF XY:

0.00240

show subpopulations

Gnomad AFR exome

AF:

0.0379

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00132

AC:

1922

AN:

1456192

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

881

AN XY:

724830

show subpopulations

African (AFR)

AF:

0.0396

AC:

1318

AN:

33276

American (AMR)

AF:

0.00134

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39514

South Asian (SAS)

AF:

0.00378

AC:

325

AN:

86086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0000307

AC:

AN:

1107258

Other (OTH)

AF:

0.00292

AC:

176

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

170

256

341

426

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.0114

AC:

1740

AN:

152324

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

831

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0396

AC:

1644

AN:

41564

American (AMR)

AF:

0.00373

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68026

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

168

252

336

420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00265

Hom.:

Bravo

AF:

0.0124

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0388

AC:

171

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00400

AC:

485

Asia WGS

AF:

0.0130

AC:

AN:

3472

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 11, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Smith-McCort dysplasia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dyggve-Melchior-Clausen syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Connective tissue disorder

Benign:1

Mar 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.95

PhyloP100

0.62

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.90

REVEL

Benign

0.21

Sift

Benign

0.45

Sift4G

Benign

0.40

Polyphen

0.0

Vest4

0.090

MVP

0.66

MPC

0.066

ClinPred

0.0072

GERP RS

1.6

PromoterAI

0.075

Neutral

(source)

Varity_R

0.028

gMVP

0.062

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00077

dbscSNV1_RF

Benign

0.072

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over