rs72656340

Positions:

• chr17-50186664-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_000088.4(COL1A1):​c.3790A>G​(p.Met1264Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.749

Genes affected

COL1A1 (HGNC:2197): (collagen type I alpha 1 chain) This gene encodes the pro-alpha1 chains of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. Reciprocal translocations between chromosomes 17 and 22, where this gene and the gene for platelet-derived growth factor beta are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans, resulting from unregulated expression of the growth factor. Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a disulfide_bond (size 32) in uniprot entity CO1A1_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000088.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL1A1. . Gene score misZ 3.5319 (greater than the threshold 3.09). Trascript score misZ 5.7733 (greater than threshold 3.09). GenCC has associacion of gene with Caffey disease, Ehlers-Danlos/osteogenesis imperfecta syndrome, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, Ehlers-Danlos syndrome, arthrochalasia type, osteogenesis imperfecta type 3, Ehlers-Danlos syndrome, classic type, 1, high bone mass osteogenesis imperfecta, osteogenesis imperfecta type 4, Ehlers-Danlos syndrome, classic type, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-50186664-T-C is Pathogenic according to our data. Variant chr17-50186664-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 425625.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-50186664-T-C is described in Lovd as [Pathogenic]. Variant chr17-50186664-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.3790A>G	p.Met1264Val	missense_variant	48/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.3592A>G	p.Met1198Val	missense_variant	45/48		XP_011522643.1
COL1A1	XM_005257058.5	c.3520A>G	p.Met1174Val	missense_variant	46/49		XP_005257115.2
COL1A1	XM_005257059.5	c.2872A>G	p.Met958Val	missense_variant	35/38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.3790A>G	p.Met1264Val	missense_variant	48/51	1	NM_000088.4	ENSP00000225964	P1
COL1A1	ENST00000510710.3	n.459A>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type I Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 10, 2019	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 15235039). This variant has been observed in individuals affected with osteogenesis imperfecta (OI) or with clinical features of both OI and Ehlers-Danlos syndrome (PMID: 15235039, 26177859, Invitae). In at least one of these individuals the variant was found to be de novo. It was also observed to segregate with disease in related individuals (Invitae). ClinVar contains an entry for this variant (Variation ID: 425625). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 1264 of the COL1A1 protein (p.Met1264Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. -
Pathogenic, no assertion criteria provided	clinical testing	Department of Medical Sciences, Uppsala University	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Benign	-0.096
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.011	D
Sift4G	Benign	0.068	T
Vest4		0.89
MutPred		0.76		Gain of methylation at K1263 (P = 0.0172);
MVP		0.94
MPC		0.57
ClinPred		0.56	D
GERP RS		3.9
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs72656340; hg19: chr17-48264025;