1-150512368-A-T

Variant names:

• chr1-150512368-A-T
• rs151102225
• NM_004425.4:c.1100A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004425.4(ECM1):​c.1100A>T​(p.Asp367Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00987 in 1,612,804 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (7 hom., cov: 27)
  • Exomes 𝑓: 0.010 (92 hom.)
• Consequence: ECM1 NM_004425.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.59
• Publications: 8 publications found

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

ENSG00000307101 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.015558243).
• BP6: Variant 1-150512368-A-T is Benign according to our data. Variant chr1-150512368-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376771.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 = 0.00728 (1098/150920) while in subpopulation NFE AF = 0.0117 (792/67776). AF 95% confidence interval is 0.011. There are 7 homozygotes in GnomAd4. There are 528 alleles in the male GnomAd4 subpopulation. Median coverage is 27. 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECM1	NM_004425.4	MANE Select	c.1100A>T	p.Asp367Val	missense	Exon 8 of 10	NP_004416.2
	ECM1	NM_001202858.2		c.1181A>T	p.Asp394Val	missense	Exon 8 of 10	NP_001189787.1
	ECM1	NM_022664.3		c.725A>T	p.Asp242Val	missense	Exon 7 of 9	NP_073155.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECM1	ENST00000369047.9	TSL:1 MANE Select	c.1100A>T	p.Asp367Val	missense	Exon 8 of 10	ENSP00000358043.4
	ECM1	ENST00000346569.6	TSL:1	c.725A>T	p.Asp242Val	missense	Exon 7 of 9	ENSP00000271630.6
	ECM1	ENST00000369049.8	TSL:2	c.1181A>T	p.Asp394Val	missense	Exon 8 of 10	ENSP00000358045.4

Frequencies

GnomAD3 genomes AF: 0.00729 AC: 1099 AN: 150802 Hom.: 7 Cov.: 27

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00612

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00468

Gnomad FIN AF: 0.00460

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.00338

GnomAD2 exomes AF: 0.00729 AC: 1828 AN: 250644 AF XY: 0.00749

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00332

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00504

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00782

GnomAD4 exome AF: 0.0101 AC: 14825 AN: 1461884 Hom.: 92 Cov.: 32 AF XY: 0.00993 AC XY: 7221 AN XY: 727244

African (AFR) AF: 0.00143 AC: 48 AN: 33480

American (AMR) AF: 0.00349 AC: 156 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 418 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00599 AC: 517 AN: 86258

European-Finnish (FIN) AF: 0.00603 AC: 322 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0115 AC: 12809 AN: 1112002

Other (OTH) AF: 0.00911 AC: 550 AN: 60396

GnomAD4 genome AF: 0.00728 AC: 1098 AN: 150920 Hom.: 7 Cov.: 27 AF XY: 0.00717 AC XY: 528 AN XY: 73632

African (AFR) AF: 0.00202 AC: 83 AN: 41088

American (AMR) AF: 0.00605 AC: 91 AN: 15044

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00468 AC: 22 AN: 4696

European-Finnish (FIN) AF: 0.00460 AC: 48 AN: 10440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0117 AC: 792 AN: 67776

Other (OTH) AF: 0.00334 AC: 7 AN: 2096

Alfa AF: 0.00943 Hom.: 1

Bravo AF: 0.00651

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0109 AC: 94

ExAC AF: 0.00773 AC: 939

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00862

EpiControl AF: 0.00925

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Dec 30, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ECM1: BS1, BS2

Lipid proteinosis Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.6
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.64
MVP		0.95
MPC		0.62
ClinPred		0.032	T
GERP RS		4.6
Varity_R		0.67
gMVP		0.75
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs151102225; hg19: chr1-150484844;