1-150509686-A-C

Variant names:

• chr1-150509686-A-C
• rs1364726581
• NM_004425.4:c.147A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_004425.4(ECM1):​c.147A>C​(p.Pro49Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00036 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ECM1 NM_004425.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.250
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P

ENSG00000307101 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-150509686-A-C is Benign according to our data. Variant chr1-150509686-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 789433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.25 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECM1	NM_004425.4	MANE Select	c.147A>C	p.Pro49Pro	synonymous	Exon 3 of 10	NP_004416.2	A0A140VJI7
	ECM1	NM_001202858.2		c.147A>C	p.Pro49Pro	synonymous	Exon 3 of 10	NP_001189787.1	Q16610-4
	ECM1	NM_022664.3		c.147A>C	p.Pro49Pro	synonymous	Exon 3 of 9	NP_073155.2	Q16610-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECM1	ENST00000369047.9	TSL:1 MANE Select	c.147A>C	p.Pro49Pro	synonymous	Exon 3 of 10	ENSP00000358043.4	Q16610-1
	ECM1	ENST00000346569.6	TSL:1	c.147A>C	p.Pro49Pro	synonymous	Exon 3 of 9	ENSP00000271630.6	Q16610-2
	ECM1	ENST00000855847.1		c.147A>C	p.Pro49Pro	synonymous	Exon 3 of 10	ENSP00000525906.1

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 206 AN: 121494 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00392

Gnomad AMR AF: 0.00127

Gnomad ASJ AF: 0.00102

Gnomad EAS AF: 0.00103

Gnomad SAS AF: 0.000574

Gnomad FIN AF: 0.00152

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.00181

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251258 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000361 AC: 332 AN: 919218 Hom.: 0 Cov.: 33 AF XY: 0.000355 AC XY: 166 AN XY: 468150

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000462 AC: 10 AN: 21668

American (AMR) AF: 0.000182 AC: 7 AN: 38460

Ashkenazi Jewish (ASJ) AF: 0.000414 AC: 7 AN: 16920

East Asian (EAS) AF: 0.000350 AC: 7 AN: 20014

South Asian (SAS) AF: 0.000157 AC: 12 AN: 76248

European-Finnish (FIN) AF: 0.000228 AC: 8 AN: 35018

Middle Eastern (MID) AF: 0.000247 AC: 1 AN: 4050

European-Non Finnish (NFE) AF: 0.000393 AC: 264 AN: 670916

Other (OTH) AF: 0.000445 AC: 16 AN: 35924

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00169 AC: 205 AN: 121600 Hom.: 0 Cov.: 30 AF XY: 0.00202 AC XY: 118 AN XY: 58478

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00194 AC: 62 AN: 31934

American (AMR) AF: 0.00127 AC: 15 AN: 11818

Ashkenazi Jewish (ASJ) AF: 0.00102 AC: 3 AN: 2930

East Asian (EAS) AF: 0.00103 AC: 4 AN: 3882

South Asian (SAS) AF: 0.000286 AC: 1 AN: 3492

European-Finnish (FIN) AF: 0.00152 AC: 11 AN: 7256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.00179 AC: 103 AN: 57588

Other (OTH) AF: 0.00179 AC: 3 AN: 1674

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0305 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.1
DANN	Benign	0.73
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1364726581; hg19: chr1-150482162;