rs193922139

Positions:

• chr17-50195227-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The ENST00000225964.10(COL1A1):​c.1299+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL1A1 ENST00000225964.10 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.81

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 4: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, phyloP100way_vertebrate [when BayesDel_noAF was below the threshold]
• PP5: Variant 17-50195227-C-T is Pathogenic according to our data. Variant chr17-50195227-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50195227-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-50195227-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.1299+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000225964.10	NP_000079.2
COL1A1	XM_005257058.5	c.1299+5G>A		splice_donor_5th_base_variant, intron_variant			XP_005257115.2
COL1A1	XM_005257059.5	c.957+1087G>A		intron_variant			XP_005257116.2
COL1A1	XM_011524341.2	c.1101+5G>A		splice_donor_5th_base_variant, intron_variant			XP_011522643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.1299+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_000088.4	ENSP00000225964	P1
COL1A1	ENST00000471344.1	n.243+5G>A		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type I Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 18, 2022	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 35900). This variant is also known as IVS19+5G>A. This variant has been observed in individuals with osteogenesis imperfecta (PMID: 25963598; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 19 of the COL1A1 gene. It does not directly change the encoded amino acid sequence of the COL1A1 protein. It affects a nucleotide within the consensus splice site. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 03, 2018	- -

Osteogenesis imperfecta Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 22, 2019

Variant summary: COL1A1 c.1299+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site (ACMG PP3). However, these predictions have yet to be confirmed by functional studies. The variant was absent in 241188 control chromosomes (ACMG PM2). c.1299+5G>A has been reported in the literature in at-least two individuals affected with Osteogenesis Imperfecta type I (Schleit_2015) (ACMG PS4). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2022

The c.1299+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 19 in the COL1A1 gene. This variant has been reported in the literature in individuals reported to have osteogenesis imperfecta (OI) and has been observed in at least one additional individual with a personal and/or family history consistent with OI (Schleit J et al. Hum Mutat, 2015 Jul;36:728-39; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.76		Position offset: 13
DS_DL_spliceai		0.88		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922139; hg19: chr17-48272588;