17-50199903-G-A

Variant names:

• chr17-50199903-G-A
• rs1555575425
• NM_000088.4:c.148C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000088.4(COL1A1):​c.148C>T​(p.Arg50*) variant causes a stop gained 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL1A1 NM_000088.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.96

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 12 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 17-50199903-G-A is Pathogenic according to our data. Variant chr17-50199903-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 504445.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-50199903-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.148C>T	p.Arg50*	stop_gained	Exon 2 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.148C>T	p.Arg50*	stop_gained	Exon 2 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.148C>T	p.Arg50*	stop_gained	Exon 2 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.148C>T	p.Arg50*	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.148C>T	p.Arg50*	stop_gained	Exon 2 of 51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000507689.1	c.202C>T	p.Arg68*	stop_gained	Exon 1 of 4	2		ENSP00000460459.1
COL1A1	ENST00000474644.1	n.267C>T		non_coding_transcript_exon_variant	Exon 2 of 4	3
ENSG00000249406	ENST00000509943.2	n.28G>A		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

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Oct 01, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31064048, 28725987) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.23
Eigen_PC	Benign	-0.047
FATHMM_MKL	Benign	0.71	D
Vest4		0.74
GERP RS		-1.8

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: rs1555575425; hg19: chr17-48277264;