rs72648326

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000088.4(COL1A1):​c.1243C>T​(p.Arg415Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R415R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

COL1A1
NM_000088.4 stop_gained

Scores

3
3
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:1

Conservation

PhyloP100: 8.13
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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 17-50195288-G-A is Pathogenic according to our data. Variant chr17-50195288-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 425597.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=7, Uncertain_significance=1}. Variant chr17-50195288-G-A is described in Lovd as [Likely_pathogenic]. Variant chr17-50195288-G-A is described in Lovd as [Pathogenic]. Variant chr17-50195288-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL1A1NM_000088.4 linkuse as main transcriptc.1243C>T p.Arg415Ter stop_gained 19/51 ENST00000225964.10
COL1A1XM_011524341.2 linkuse as main transcriptc.1045C>T p.Arg349Ter stop_gained 16/48
COL1A1XM_005257058.5 linkuse as main transcriptc.1243C>T p.Arg415Ter stop_gained 19/49
COL1A1XM_005257059.5 linkuse as main transcriptc.957+1026C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL1A1ENST00000225964.10 linkuse as main transcriptc.1243C>T p.Arg415Ter stop_gained 19/511 NM_000088.4 P1
COL1A1ENST00000471344.1 linkuse as main transcriptn.187C>T non_coding_transcript_exon_variant 3/82

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461624
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
727114
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:9Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 08, 2024Nonsense 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: 36709916, 37270749, 31447884, 27132807, 15741671, 8613526, 22679784, 8808594, 27748872, 31414283, 31363794, 15024745, 25944380, 31794058, 32166892, 33939306, 35909573, 35822426, 35186396, 37334733, 27535533) -
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsJun 21, 2017- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityDec 02, 2022- -
Osteogenesis imperfecta type I Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024This sequence change creates a premature translational stop signal (p.Arg415*) 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 individuals with osteogenesis imperfecta, type 1 (PMID: 8613526, 8808594, 15024745, 25944380, 27132807). ClinVar contains an entry for this variant (Variation ID: 425597). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedclinical testingDepartment of Medical Sciences, Uppsala University-- -
Infantile cortical hyperostosis;C0023931:Osteogenesis imperfecta type I;C0029456:Osteoporosis;C0268358:Osteogenesis imperfecta, perinatal lethal;C0268362:Osteogenesis imperfecta type III;C0268363:Osteogenesis imperfecta with normal sclerae, dominant form;C4551623:Ehlers-Danlos syndrome, arthrochalasia type;C5436842:Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 24, 2021- -
COL1A1-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 23, 2024The COL1A1 c.1243C>T variant is predicted to result in premature protein termination (p.Arg415*). This variant was reported in multiple individuals with osteogenesis imperfecta (see example: Higuchi et al. 2021. PubMed ID: 33939306; Hruskova et al. 2016. PubMed ID: 27132807; Morlino et al. 2020. PubMed ID: 31794058). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in COL1A1 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testing3billion-The variant is not observed in the gnomAD v2.1.1 dataset. The variant is 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. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000425597 / PMID: 8808594). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Infantile cortical hyperostosis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
Osteogenesis imperfecta, perinatal lethal Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGMJun 02, 2023The observed missense c.496G>A (p.Val166Ile) variant in POLR3A gene has been previously reported in compound heterozygous state in individuals affected with Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism (Wolf NI et al. 2014). The p.Val166Ile variant has allele frequency 0.005% gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. Multiple lines of computational evidence (Polyphen -Probably damaging, SIFT - Tolerated and Mutation Taster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid on POLR3A gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant has been reported to the ClinVar database as Uncertain_significance with a status of criteria provided, single submitter. The amino acid change p.Val166Ile in POLR3A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
40
DANN
Uncertain
1.0
Eigen
Pathogenic
0.79
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.89
D
MutationTaster
Benign
1.0
A
Vest4
0.89
GERP RS
4.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs72648326; hg19: chr17-48272649; API