Variant 1-150509675-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004425.4(ECM1):c.136C>G(p.Pro46Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ECM1
NM_004425.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.755

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26461792).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ECM1	NM_004425.4 linkuse as main transcript	c.136C>G	p.Pro46Ala	missense_variant	3/10	ENST00000369047.9
ECM1	NM_001202858.2 linkuse as main transcript	c.136C>G	p.Pro46Ala	missense_variant	3/10
ECM1	NM_022664.3 linkuse as main transcript	c.136C>G	p.Pro46Ala	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECM1	ENST00000369047.9 linkuse as main transcript	c.136C>G	p.Pro46Ala	missense_variant	3/10	1	NM_004425.4	P1	Q16610-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000344

AC:

AN:

1455266

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724306

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000362

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2022

The c.136C>G (p.P46A) alteration is located in exon 3 (coding exon 3) of the ECM1 gene. This alteration results from a C to G substitution at nucleotide position 136, causing the proline (P) at amino acid position 46 to be replaced by an alanine (A). 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

Benign

0.10

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.34

.;T;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.75

T;T;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.8

L;L;L

MutationTaster

Benign

0.90

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.9

D;D;D

REVEL

Benign

0.24

Sift

Benign

0.060

T;T;T

Sift4G

Benign

0.12

T;T;T

Polyphen

0.41

B;B;B

Vest4

0.41

MutPred

0.61

Loss of glycosylation at P46 (P = 0.0096);Loss of glycosylation at P46 (P = 0.0096);Loss of glycosylation at P46 (P = 0.0096);

MVP

0.85

MPC

0.13

ClinPred

0.73

GERP RS

2.3

Varity_R

0.086

gMVP

0.27

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over