rs72656314

Positions:

• chr17-50187486-G-A
• chr17-50187486-G-T

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.3421C>T​(p.Arg1141Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1141R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: COL1A1 NM_000088.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9816
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.45

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 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 17-50187486-G-A is Pathogenic according to our data. Variant chr17-50187486-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50187486-G-A is described in Lovd as [Pathogenic]. Variant chr17-50187486-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.3421C>T	p.Arg1141Ter	stop_gained, splice_region_variant	46/51	ENST00000225964.10
COL1A1	XM_011524341.2	c.3223C>T	p.Arg1075Ter	stop_gained, splice_region_variant	43/48
COL1A1	XM_005257058.5	c.3151C>T	p.Arg1051Ter	stop_gained, splice_region_variant	44/49
COL1A1	XM_005257059.5	c.2503C>T	p.Arg835Ter	stop_gained, splice_region_variant	33/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.3421C>T	p.Arg1141Ter	stop_gained, splice_region_variant	46/51	1	NM_000088.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74296

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	The COL1A1 c.3421C>T; p.Arg1141Ter variant (rs72656314) is reported in the literature in individuals affected with osteogenesis imperfecta (Balasubramanian 2016, Bardai 2017, Chen 2022, Higuchi 1994, Mei 2022, Tuysuz 2022, Willing 1994). This variant is also reported in ClinVar (Variation ID: 17337), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Balasubramanian M et al. Osteogenesis imperfecta: Ultrastructural and histological findings on examination of skin revealing novel insights into genotype-phenotype correlation. Ultrastruct Pathol. 2016;40(2):71-6. PMID: 26863094. Bardai G et al. Molecular diagnosis in children with fractures but no extraskeletal signs of osteogenesis imperfecta. Osteoporos Int. 2017 Jul;28(7):2095-2101. PMID: 28378289. Chen P et al. Phenotypic Spectrum and Molecular Basis in a Chinese Cohort of Osteogenesis Imperfecta With Mutations in Type I Collagen. Front Genet. 2022 Jan 28;13:816078. PMID: 35154279. Higuchi Y et al. Genetic analysis in Japanese patients with osteogenesis imperfecta: Genotype and phenotype spectra in 96 probands. Mol Genet Genomic Med. 2021 Jun;9(6):e1675. PMID: 33939306. Mei Y et al. Comparing Clinical and Genetic Characteristics of De Novo and Inherited COL1A1/COL1A2 Variants in a Large Chinese Cohort of Osteogenesis Imperfecta. Front Endocrinol (Lausanne). 2022 Jul 14;13:935905. PMID: 35909573. Tuysuz B et al. Osteogenesis imperfecta in 140 Turkish families: Molecular spectrum and, comparison of long-term clinical outcome of those with COL1A1/A2 and biallelic variants. Bone. 2022 Feb;155:116293. PMID: 34902613. Willing MC et al. Osteogenesis imperfecta type I: molecular heterogeneity for COL1A1 null alleles of type I collagen. Am J Hum Genet. 1994 Oct;55(4):638-47. PMID: 7942841. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2022	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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7942841, 9067755, 25525159, 26863094, 25436829, 16879195, 25214535, 28882457, 18311573, 28378289, 16705691, 32123938, 33939306) -

Osteogenesis imperfecta type I Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000017337, PMID:7942841). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	This sequence change creates a premature translational stop signal (p.Arg1141*) 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 osteogenesis imperfecta (PMID: 7942841, 9067755, 16705691, 28378289). ClinVar contains an entry for this variant (Variation ID: 17337). For these reasons, this variant has been classified as Pathogenic. -

Osteogenesis imperfecta Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jun 30, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Nov 01, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	50
DANN	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	A
Vest4		0.95
GERP RS		3.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.69
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: rs72656314; hg19: chr17-48264847; COSMIC: COSV56802240; COSMIC: COSV56802240;