NM_004425.4:c.118G>A

Variant names:

• chr1-150509578-G-A
• NM_004425.4:c.118G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004425.4(ECM1):​c.118G>A​(p.Glu40Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ECM1 NM_004425.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P

ENSG00000307101 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.118G>A	p.Glu40Lys	missense	Exon 2 of 10	NP_004416.2	A0A140VJI7
	ECM1	NM_001202858.2		c.118G>A	p.Glu40Lys	missense	Exon 2 of 10	NP_001189787.1	Q16610-4
	ECM1	NM_022664.3		c.118G>A	p.Glu40Lys	missense	Exon 2 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.118G>A	p.Glu40Lys	missense	Exon 2 of 10	ENSP00000358043.4	Q16610-1
	ECM1	ENST00000346569.6	TSL:1	c.118G>A	p.Glu40Lys	missense	Exon 2 of 9	ENSP00000271630.6	Q16610-2
	ECM1	ENST00000855847.1		c.118G>A	p.Glu40Lys	missense	Exon 2 of 10	ENSP00000525906.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.22	T
Polyphen		0.89	P
Vest4		0.39
MutPred		0.60		Gain of methylation at E40 (P = 0.0013)
MVP		0.91
MPC		0.55
ClinPred		0.86	D
GERP RS		3.2
Varity_R		0.15
gMVP		0.58
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

hg19: chr1-150482054;