rs13294

Positions:

• chr1-150512511-G-A
• chr1-150512511-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004425.4(ECM1):​c.1243G>A​(p.Gly415Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 1,613,130 control chromosomes in the GnomAD database, including 121,478 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.33 (9096 hom., cov: 28)
  • Exomes 𝑓: 0.39 (112382 hom.)
• Consequence: ECM1 NM_004425.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.878

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036849082).
• BP6: Variant 1-150512511-G-A is Benign according to our data. Variant chr1-150512511-G-A is described in ClinVar as [Benign]. Clinvar id is 1255367.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-150512511-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECM1	NM_004425.4	c.1243G>A	p.Gly415Ser	missense_variant	8/10	ENST00000369047.9
ECM1	NM_001202858.2	c.1324G>A	p.Gly442Ser	missense_variant	8/10
ECM1	NM_022664.3	c.868G>A	p.Gly290Ser	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECM1	ENST00000369047.9	c.1243G>A	p.Gly415Ser	missense_variant	8/10	1	NM_004425.4	P1
ECM1	ENST00000346569.6	c.868G>A	p.Gly290Ser	missense_variant	7/9	1
ECM1	ENST00000369049.8	c.1324G>A	p.Gly442Ser	missense_variant	8/10	2
ECM1	ENST00000470432.5	n.2600G>A		non_coding_transcript_exon_variant	4/6	2

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50422 AN: 151166 Hom.: 9088 Cov.: 28

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.361

GnomAD3 exomes AF: 0.352 AC: 88524 AN: 251444 Hom.: 16631 AF XY: 0.359 AC XY: 48816 AN XY: 135890

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.506

Gnomad EAS exome AF: 0.234

Gnomad SAS exome AF: 0.341

Gnomad FIN exome AF: 0.415

Gnomad NFE exome AF: 0.406

Gnomad OTH exome AF: 0.391

GnomAD4 exome AF: 0.387 AC: 565697 AN: 1461846 Hom.: 112382 Cov.: 75 AF XY: 0.388 AC XY: 282325 AN XY: 727226

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.233

Gnomad4 ASJ exome AF: 0.497

Gnomad4 EAS exome AF: 0.260

Gnomad4 SAS exome AF: 0.341

Gnomad4 FIN exome AF: 0.418

Gnomad4 NFE exome AF: 0.403

Gnomad4 OTH exome AF: 0.384

GnomAD4 genome AF: 0.333 AC: 50448 AN: 151284 Hom.: 9096 Cov.: 28 AF XY: 0.332 AC XY: 24510 AN XY: 73846

Gnomad4 AFR AF: 0.204

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.508

Gnomad4 EAS AF: 0.246

Gnomad4 SAS AF: 0.330

Gnomad4 FIN AF: 0.410

Gnomad4 NFE AF: 0.405

Gnomad4 OTH AF: 0.363

Alfa AF: 0.392 Hom.: 29304

Bravo AF: 0.317

TwinsUK AF: 0.406 AC: 1504

ALSPAC AF: 0.389 AC: 1500

ESP6500AA AF: 0.208 AC: 917

ESP6500EA AF: 0.411 AC: 3534

ExAC AF: 0.353 AC: 42837

Asia WGS AF: 0.342 AC: 1189 AN: 3478

EpiCase AF: 0.408

EpiControl AF: 0.412

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lipid proteinosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.76
DEOGEN2	Benign	0.080	.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.47	T;T;T
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.9	.;N;.
MutationTaster	Benign	0.91	P;P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	2.8	N;N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0030	B;B;B
Vest4		0.056
MPC		0.10
ClinPred		0.0030	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.43

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

Other links and lift over

dbSNP: rs13294; hg19: chr1-150484987; COSMIC: COSV60873269; COSMIC: COSV60873269;