17-50191978-A-T

Variant names:

• chr17-50191978-A-T
• NM_000088.4:c.2028+2T>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000088.4(COL1A1):​c.2028+2T>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL1A1 NM_000088.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.19

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.010238908 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5, offset of 4, new splice context is: aaaGTaggc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-50191978-A-T is Pathogenic according to our data. Variant chr17-50191978-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 1996325.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.2028+2T>A		splice_donor_variant, intron_variant	Intron 30 of 50	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.1830+2T>A		splice_donor_variant, intron_variant	Intron 27 of 47		XP_011522643.1
COL1A1	XM_005257058.5	c.2028+2T>A		splice_donor_variant, intron_variant	Intron 30 of 48		XP_005257115.2
COL1A1	XM_005257059.5	c.1110+2T>A		splice_donor_variant, intron_variant	Intron 17 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.2028+2T>A		splice_donor_variant, intron_variant	Intron 30 of 50	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000476387.1	n.377+2T>A		splice_donor_variant, intron_variant	Intron 6 of 8	2
COL1A1	ENST00000504289.1	n.460+2T>A		splice_donor_variant, intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 44

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type I Pathogenic:2

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with osteogenesis imperfect types (OI), types I-IV, and other conditions (OMIM). Variants resulting in a truncated protein are known to have a loss of function effect on protein and are usually associate with a milder phenotype. Missense variants affecting the G-X-Y of a triple helix motif have a dominant negative effect and are commonly associated with a more severe phenotype (PMID:27509835, PMID:12362985). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Interfamilial variability is apparent among individuals with the same OI type and intrafamilial variability is apparent among individuals with the same causative variant (GeneReviews). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RNA studies demonstrated the presence of an aberrant mRNA, which underwent nonsense-mediated decay (NMD). However, the exact sequence was not shown (personal communciation). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0702 - Other splice site variants comparable to the one identified in this case have strong previous evidence for pathogenicity. At least three other variants at this splice site have been reported in multiple OI individuals (PMIDs: 22206639, 29595812). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individual(s) with autosomal dominant osteogenesis imperfecta (PMID: 15241796). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 30 of the COL1A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 7942841, 9295084, 9443882). -

COL1A1-related disorder Pathogenic:1

Nov 02, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The COL1A1 c.2028+2T>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in COL1A1 are expected to be pathogenic. In addition, similar intronic variants (for examples: c.2028+1G>A, c.2028+2T>G) were reported to be pathogenic (Hartikka et al. 2004. PubMed ID: 15241796; Swinnen et al. 2011. PubMed ID: 22206639). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.97	D
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.88		Position offset: -30
DS_DL_spliceai		0.99		Position offset: 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: chr17-48269339;