1-150509578-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECM1	NM_004425.4	c.118G>A	p.Glu40Lys	missense_variant	2/10	ENST00000369047.9
ECM1	NM_001202858.2	c.118G>A	p.Glu40Lys	missense_variant	2/10
ECM1	NM_022664.3	c.118G>A	p.Glu40Lys	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECM1	ENST00000369047.9	c.118G>A	p.Glu40Lys	missense_variant	2/10	1	NM_004425.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The c.118G>A (p.E40K) alteration is located in exon 2 (coding exon 2) of the ECM1 gene. This alteration results from a G to A substitution at nucleotide position 118, causing the glutamic acid (E) at amino acid position 40 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	0.56	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0070	D;D;D
Sift4G	Benign	0.22	T;T;T
Polyphen		0.89	P;D;D
Vest4		0.39
MutPred		0.60		Gain of methylation at E40 (P = 0.0013);Gain of methylation at E40 (P = 0.0013);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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-150482054;