17-50199917-AG-C

Variant names:

• chr17-50199917-AG-C
• NM_000088.4:c.133_134delCTinsG

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PM2 PP2 PP5_Moderate

The NM_000088.4(COL1A1):​c.133_134delCTinsG​(p.Leu45AlafsTer29) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 frameshift, missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.47

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 13 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
• PP2: Missense variant in the COL1A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 368 curated pathogenic missense variants (we use a threshold of 10). The gene has 98 curated benign missense variants. Gene score misZ: 3.5319 (above the threshold of 3.09). Trascript score misZ: 5.7733 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• PP5: Variant 17-50199917-AG-C is Pathogenic according to our data. Variant chr17-50199917-AG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1701325.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.133_134delCTinsG	p.Leu45AlafsTer29	frameshift_variant, missense_variant	Exon 2 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.133_134delCTinsG	p.Leu45AlafsTer29	frameshift_variant, missense_variant	Exon 2 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.133_134delCTinsG	p.Leu45AlafsTer29	frameshift_variant, missense_variant	Exon 2 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.133_134delCTinsG	p.Leu45AlafsTer29	frameshift_variant, missense_variant	Exon 2 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.133_134delCTinsG	p.Leu45AlafsTer29	frameshift_variant, missense_variant	Exon 2 of 51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000507689.1	c.187_188delCTinsG	p.Leu63AlafsTer29	frameshift_variant, missense_variant	Exon 1 of 4	2		ENSP00000460459.1
COL1A1	ENST00000474644.1	n.252_253delCTinsG		non_coding_transcript_exon_variant	Exon 2 of 4	3
ENSG00000249406	ENST00000509943.2	n.42_43delAGinsC		non_coding_transcript_exon_variant	Exon 1 of 7	3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Mar 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Splicing

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: chr17-48277278;