rs768474010

Variant names:

• chr1-150509926-GC-G
• rs768474010
• NM_004425.4:c.233delC

Your query was ambiguous. Multiple possible variants found:

• chr1-150509926-GC-G
• chr1-150509926-GC-GCC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_004425.4(ECM1):​c.233delC​(p.Pro78LeufsTer100) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: ECM1 NM_004425.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.0540
• Publications: 1 publications found

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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ENSG00000307101 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-150509926-GC-G is Pathogenic according to our data. Variant chr1-150509926-GC-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1034085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004425.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECM1	NM_004425.4	MANE Select	c.233delC	p.Pro78LeufsTer100	frameshift	Exon 4 of 10	NP_004416.2	A0A140VJI7
	ECM1	NM_001202858.2		c.314delC	p.Pro105LeufsTer100	frameshift	Exon 4 of 10	NP_001189787.1	Q16610-4
	ECM1	NM_022664.3		c.233delC	p.Pro78LeufsTer100	frameshift	Exon 4 of 9	NP_073155.2	Q16610-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECM1	ENST00000369047.9	TSL:1 MANE Select	c.233delC	p.Pro78LeufsTer100	frameshift	Exon 4 of 10	ENSP00000358043.4	Q16610-1
	ECM1	ENST00000346569.6	TSL:1	c.233delC	p.Pro78LeufsTer100	frameshift	Exon 4 of 9	ENSP00000271630.6	Q16610-2
	ECM1	ENST00000855847.1		c.320delC	p.Pro107LeufsTer100	frameshift	Exon 4 of 10	ENSP00000525906.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000915 AC: 23 AN: 251380 AF XY: 0.0000957

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: 0.000185

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000127 AC: 185 AN: 1461838 Hom.: 0 Cov.: 36 AF XY: 0.000120 AC XY: 87 AN XY: 727218

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000144 AC: 160 AN: 1111968

Other (OTH) AF: 0.000116 AC: 7 AN: 60394

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74280

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68000

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.0000364 Hom.: 0

Bravo AF: 0.0000793

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Lipid proteinosis (2)
1	-	-	ECM1-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.054
Mutation Taster		=20/180	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 2

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

Other links and lift over

dbSNP: rs768474010; hg19: chr1-150482402;