17-50199892-C-T

Variant names:

• chr17-50199892-C-T
• NM_000088.4:c.159G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000088.4(COL1A1):​c.159G>A​(p.Trp53*) variant causes a stop gained change. 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL1A1 NM_000088.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.03

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]

ENSG00000249406 (HGNC:52795): (long intergenic non-protein coding RNA 1969)

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-50199892-C-T is Pathogenic according to our data. Variant chr17-50199892-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2849807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.159G>A	p.Trp53*	stop_gained	Exon 2 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.159G>A	p.Trp53*	stop_gained	Exon 2 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.159G>A	p.Trp53*	stop_gained	Exon 2 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.159G>A	p.Trp53*	stop_gained	Exon 2 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.159G>A	p.Trp53*	stop_gained	Exon 2 of 51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000507689.1	c.213G>A	p.Trp71*	stop_gained	Exon 1 of 4	2		ENSP00000460459.1
COL1A1	ENST00000474644.1	n.278G>A		non_coding_transcript_exon_variant	Exon 2 of 4	3
ENSG00000249406	ENST00000509943.2	n.17C>T		non_coding_transcript_exon_variant	Exon 1 of 7	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, arthrochalasia type Pathogenic:1

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed stop gained variant c.159G>A(p.Trp53Ter) in COL1A1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.159G>A variant is absent in gnomAD Exomes. The reference nucleotide c.159G>A in COL1A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence (Mutation Taster - Disease causing) predicts damaging effect on protein structure and function for this variant.This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. (Körkkö J, et al., 1998). For these reasons, this variant has been classified as Likely Pathogenic. -

Osteogenesis imperfecta type I Pathogenic:1

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp53*) in the COL1A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 7942841, 9295084, 9443882). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of osteogenesis imperfecta (PMID: 30886339). ClinVar contains an entry for this variant (Variation ID: 2849807). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	41
DANN	Uncertain	0.99
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.84
GERP RS		4.6

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-48277253;