1-150509675-C-A

Variant names:

• chr1-150509675-C-A
• rs748885769
• NM_004425.4:c.136C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004425.4(ECM1):​c.136C>A​(p.Pro46Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P46A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ECM1 NM_004425.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.755

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3651071).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECM1	NM_004425.4	c.136C>A	p.Pro46Thr	missense_variant	Exon 3 of 10	ENST00000369047.9	NP_004416.2
ECM1	NM_001202858.2	c.136C>A	p.Pro46Thr	missense_variant	Exon 3 of 10		NP_001189787.1
ECM1	NM_022664.3	c.136C>A	p.Pro46Thr	missense_variant	Exon 3 of 9		NP_073155.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECM1	ENST00000369047.9	c.136C>A	p.Pro46Thr	missense_variant	Exon 3 of 10	1	NM_004425.4	ENSP00000358043.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251418 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135876

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455332 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724340

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	.;T;.
Eigen	Benign	0.039
Eigen_PC	Benign	-0.072
FATHMM_MKL	Benign	0.065	N
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.1	M;M;M
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	D;D;P
Vest4		0.34
MutPred		0.62		Gain of phosphorylation at P46 (P = 0.0203);Gain of phosphorylation at P46 (P = 0.0203);Gain of phosphorylation at P46 (P = 0.0203);
MVP		0.92
MPC		0.49
ClinPred		0.97	D
GERP RS		2.3
Varity_R		0.24
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs748885769; hg19: chr1-150482151;