1-150509669-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.29

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 Benign. Variant got -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 id is 777102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-150509669-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECM1	NM_004425.4	c.130G>A	p.Ala44Thr	missense_variant	3/10	ENST00000369047.9
ECM1	NM_001202858.2	c.130G>A	p.Ala44Thr	missense_variant	3/10
ECM1	NM_022664.3	c.130G>A	p.Ala44Thr	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECM1	ENST00000369047.9	c.130G>A	p.Ala44Thr	missense_variant	3/10	1	NM_004425.4	P1

Frequencies

GnomAD3 genomes AF: 0.00785 AC: 1193 AN: 151894 Hom.: 7 Cov.: 32

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

GnomAD3 exomes AF: 0.00721 AC: 1813 AN: 251434 Hom.: 7 AF XY: 0.00720 AC XY: 978 AN XY: 135886

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 SAS exome AF: 0.000490

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.: 81 Cov.: 31 AF XY: 0.00890 AC XY: 6473 AN XY: 727110

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00391

Gnomad4 ASJ exome AF: 0.00383

Gnomad4 EAS exome AF: 0.000705

Gnomad4 SAS exome AF: 0.000603

Gnomad4 FIN exome AF: 0.00897

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.00747

GnomAD4 genome AF: 0.00785 AC: 1193 AN: 152012 Hom.: 7 Cov.: 32 AF XY: 0.00749 AC XY: 557 AN XY: 74318

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00406

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0107

Gnomad4 NFE AF: 0.0129

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.0107 Hom.: 13

Bravo AF: 0.00723

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0110 AC: 95

ExAC AF: 0.00749 AC: 909

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0100

EpiControl AF: 0.0106

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

ECM1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.88	D;D;D
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Uncertain	0.057	D
MutationAssessor	Uncertain	2.3	M;M;M
MutationTaster	Benign	0.51	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.83
MVP		0.96
MPC		0.51
ClinPred		0.030	T
GERP RS		4.3
Varity_R		0.40
gMVP		0.49

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

LitVar

Other links and lift over

dbSNP: rs145971597; hg19: chr1-150482145; COSMIC: COSV60873931; COSMIC: COSV60873931;