rs148059981

Variant names:

• chr18-49363233-C-A
• NM_001353214.3:c.422G>T

Your query was ambiguous. Multiple possible variants found:

• chr18-49363233-C-A
• chr18-49363233-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001353214.3(DYM):​c.422G>T​(p.Ser141Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DYM NM_001353214.3 missense, splice_region
• Scores: Splicing: ADA: 0.9933
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYM	NM_001353214.3	c.422G>T	p.Ser141Ile	missense_variant, splice_region_variant	Exon 6 of 18	ENST00000675505.1	NP_001340143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYM	ENST00000675505.1	c.422G>T	p.Ser141Ile	missense_variant, splice_region_variant	Exon 6 of 18		NM_001353214.3	ENSP00000501694.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460984 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726896

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.098
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.90	L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.26
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.11	B
Vest4		0.25
MutPred		0.57		Loss of disorder (P = 0.0196);
MVP		0.78
MPC		0.14
ClinPred		0.63	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-46889603;