rs120074164

chr18-49379693-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001353214.3(DYM):c.259G>A(p.Glu87Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DYM NM_001353214.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.35

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815
• PP5: Variant 18-49379693-C-T is Pathogenic according to our data. Variant chr18-49379693-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3189.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYM	NM_001353214.3	c.259G>A	p.Glu87Lys	missense_variant	4/18	ENST00000675505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYM	ENST00000675505.1	c.259G>A	p.Glu87Lys	missense_variant	4/18		NM_001353214.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251090 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135704

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460946 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726804

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Smith-McCort dysplasia 1 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 29, 2018	The DYM c.259G>A (p.Glu87Lys) variant is a missense variant that has been reported in one study, in which it is found in a compound heterozygous state with a splice acceptor variant in a total of seven individuals from two Guamanian families. All seven individuals were diagnosed with Smith-McCort Dysplasia (Cohn et al. 2003). The unaffected mothers shared a common haplotype including the p.Glu87Lys variant, which is therefore likely to be an ancestral variant. The p.Glu87Lys variant is reported at a frequency of 0.000087 in the Latino population of the Exome Aggregation Consortium though this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Functional studies by Dimitrov et al. (2009) in HeLa cells demonstrated that the p.Glu87Lys variant displays a pattern of cellular localization similar to wild type and does not affect the protein stability. The Glu87 residue is conserved. The evidence for this variant is limited. The p.Glu87Lys variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Smith-McCort Dysplasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2003	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 3189). This missense change has been observed in individual(s) with Smith-McCort dysplasia (PMID: 12491225). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs120074164, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 87 of the DYM protein (p.Glu87Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	31
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.9	D;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.013	D;.
Polyphen		0.99	D;.
Vest4		0.95
MutPred		0.62		Gain of MoRF binding (P = 0.0048);Gain of MoRF binding (P = 0.0048);
MVP		0.93
MPC		0.44
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.60
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs120074164; hg19: chr18-46906063;