17-50190350-G-A

Position:

• chr17-50190350-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000088.4(COL1A1):​c.2428C>T​(p.Pro810Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.76

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 3 uncertain 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.2428C>T	p.Pro810Ser	missense_variant	35/51	ENST00000225964.10
COL1A1	XM_011524341.2	c.2230C>T	p.Pro744Ser	missense_variant	32/48
COL1A1	XM_005257058.5	c.2428C>T	p.Pro810Ser	missense_variant	35/49
COL1A1	XM_005257059.5	c.1510C>T	p.Pro504Ser	missense_variant	22/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.2428C>T	p.Pro810Ser	missense_variant	35/51	1	NM_000088.4	P1
COL1A1	ENST00000494334.1	n.355C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (HGMD) -

Osteogenesis imperfecta type I Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has been reported in an individual affected with osteogenesis imperfecta (PMID: 21884818). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 810 of the COL1A1 protein (p.Pro810Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.039	D
Vest4		0.56
MutPred		0.46		Gain of phosphorylation at P810 (P = 0.0082);
MVP		0.81
MPC		0.57
ClinPred		0.98	D
GERP RS		5.1
gMVP		0.73

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: rs1555572744; hg19: chr17-48267711;