NM_004425.4:c.826C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_004425.4(ECM1):​c.826C>T​(p.Gln276*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,874 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 not provided (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ECM1
NM_004425.4 stop_gained

Scores

2
3
2

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 1.01

Publications

6 publications found
Variant links:
Genes affected
ECM1 (HGNC:3153): (extracellular matrix protein 1) This gene encodes a soluble protein that is involved in endochondral bone formation, angiogenesis, and tumor biology. It also interacts with a variety of extracellular and structural proteins, contributing to the maintenance of skin integrity and homeostasis. Mutations in this gene are associated with lipoid proteinosis disorder (also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease) that is characterized by generalized thickening of skin, mucosae and certain viscera. Alternatively spliced transcript variants encoding distinct isoforms have been described for this gene. [provided by RefSeq, Feb 2011]
ECM1 Gene-Disease associations (from GenCC):
  • lipoid proteinosis
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ECM1NM_004425.4 linkc.826C>T p.Gln276* stop_gained Exon 7 of 10 ENST00000369047.9 NP_004416.2 Q16610-1A0A140VJI7
ECM1NM_001202858.2 linkc.907C>T p.Gln303* stop_gained Exon 7 of 10 NP_001189787.1 Q16610-4
ECM1NM_022664.3 linkc.708+376C>T intron_variant Intron 6 of 8 NP_073155.2 Q16610-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ECM1ENST00000369047.9 linkc.826C>T p.Gln276* stop_gained Exon 7 of 10 1 NM_004425.4 ENSP00000358043.4 Q16610-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251312
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461874
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
727238
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53406
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1112010
Other (OTH)
AF:
0.0000497
AC:
3
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
31

ClinVar

Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link

Submissions by phenotype

Lipid proteinosis Other:1
-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

South African founder variant [Hamada 2002, Van Hougenhouck-Tulleken et al 2004] -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
35
DANN
Uncertain
1.0
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Benign
0.42
N
PhyloP100
1.0
Vest4
0.71
GERP RS
3.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=0/200
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs869025563; hg19: chr1-150484050; API