Genetic Variant ECM1:p.Ala44Thr (chr1-150509669-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004425.4(ECM1):c.130G>A(p.Ala44Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00887 in 1,613,572 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0078 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0090 ( 81 hom. )

Consequence

ECM1
NM_004425.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.29

Publications

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

ECM1 links:

ENSG00000307101 (HGNC:):

ENSG00000307101 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013135403).

BP6

Variant 1-150509669-G-A is Benign according to our data. Variant chr1-150509669-G-A is described in ClinVar as Benign. ClinVar VariationId is 777102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00785 (1193/152012) while in subpopulation NFE AF = 0.0129 (874/67934). AF 95% confidence interval is 0.0122. There are 7 homozygotes in GnomAd4. There are 557 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ECM1	NM_004425.4	MANE Select	c.130G>A	p.Ala44Thr	missense	Exon 3 of 10	NP_004416.2	A0A140VJI7
ECM1	NM_001202858.2		c.130G>A	p.Ala44Thr	missense	Exon 3 of 10	NP_001189787.1	Q16610-4
ECM1	NM_022664.3		c.130G>A	p.Ala44Thr	missense	Exon 3 of 9	NP_073155.2	Q16610-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ECM1	ENST00000369047.9	TSL:1 MANE Select	c.130G>A	p.Ala44Thr	missense	Exon 3 of 10	ENSP00000358043.4	Q16610-1
ECM1	ENST00000346569.6	TSL:1	c.130G>A	p.Ala44Thr	missense	Exon 3 of 9	ENSP00000271630.6	Q16610-2
ECM1	ENST00000855847.1		c.130G>A	p.Ala44Thr	missense	Exon 3 of 10	ENSP00000525906.1

Frequencies

GnomAD3 genomes

AF:

0.00785

AC:

1193

AN:

151894

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00172

Gnomad AMI

AF:

0.0493

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0107

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0129

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.00721

AC:

1813

AN:

251434

AF XY:

0.00720

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00364

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.00201

Gnomad FIN exome

AF:

0.00933

Gnomad NFE exome

AF:

0.0117

Gnomad OTH exome

AF:

0.00880

GnomAD4 exome

AF:

0.00898

AC:

13122

AN:

1461560

Hom.:

Cov.:

AF XY:

0.00890

AC XY:

6473

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.00146

AC:

AN:

33472

American (AMR)

AF:

0.00391

AC:

175

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00383

AC:

100

AN:

26136

East Asian (EAS)

AF:

0.000705

AC:

AN:

39698

South Asian (SAS)

AF:

0.000603

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00897

AC:

479

AN:

53416

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0106

AC:

11781

AN:

1111702

Other (OTH)

AF:

0.00747

AC:

451

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

730

1460

2191

2921

3651

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

382

764

1146

1528

1910

<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

AF:

0.00785

AC:

1193

AN:

152012

Hom.:

Cov.:

AF XY:

0.00749

AC XY:

557

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

41442

American (AMR)

AF:

0.00406

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.00155

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0107

AC:

113

AN:

10598

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0129

AC:

874

AN:

67934

Other (OTH)

AF:

0.00474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

129

193

258

322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0101

Hom.:

Bravo

AF:

0.00723

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0110

AC:

ExAC

AF:

0.00749

AC:

909

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0100

EpiControl

AF:

0.0106

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

ECM1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.47

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Benign

0.76

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.057

MutationAssessor

Uncertain

2.3

PhyloP100

4.3

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.83

MVP

0.96

MPC

0.51

ClinPred

0.030

GERP RS

4.3

Varity_R

0.40

gMVP

0.49

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over