chr17-50186913-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000088.4(COL1A1):​c.3541G>A​(p.Gly1181Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G1181G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

COL1A1
NM_000088.4 missense

Scores

9
4
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.13
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 4 uncertain in NM_000088.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL1A1. . Gene score misZ 3.5319 (greater than the threshold 3.09). Trascript score misZ 5.7733 (greater than threshold 3.09). GenCC has associacion of gene with 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 17-50186913-C-T is Pathogenic according to our data. Variant chr17-50186913-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50186913-C-T is described in Lovd as [Pathogenic]. Variant chr17-50186913-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL1A1NM_000088.4 linkuse as main transcriptc.3541G>A p.Gly1181Ser missense_variant 48/51 ENST00000225964.10
COL1A1XM_011524341.2 linkuse as main transcriptc.3343G>A p.Gly1115Ser missense_variant 45/48
COL1A1XM_005257058.5 linkuse as main transcriptc.3271G>A p.Gly1091Ser missense_variant 46/49
COL1A1XM_005257059.5 linkuse as main transcriptc.2623G>A p.Gly875Ser missense_variant 35/38

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL1A1ENST00000225964.10 linkuse as main transcriptc.3541G>A p.Gly1181Ser missense_variant 48/511 NM_000088.4 P1
COL1A1ENST00000510710.3 linkuse as main transcriptn.210G>A non_coding_transcript_exon_variant 1/22

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461446
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
726990
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00210
Hom.:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJan 27, 2020The COL1A1 c.3541G>A; p.Gly1181Ser variant (rs72656330) is reported in the literature in an individual affected with osteogenesis imperfecta (Pruchno 1991). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 1181 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. This codon is located in a triple helix repeat domain, and glycine substitutions are the most frequent pathogenic alterations in this region (Ben Amor 2011). Based on available information, this variant is considered to be likely pathogenic. References: Ben Amor I et al. Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos. 2011; 2011:540178. Pruchno CJ et al. Osteogenesis imperfecta due to recurrent point mutations at CpG dinucleotides in the COL1A1 gene of type I collagen. Hum Genet. 1991 May;87(1):33-40. -
Osteogenesis imperfecta, perinatal lethal Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 11, 1996- -
Osteogenesis imperfecta type I Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsDec 27, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
26
DANN
Benign
0.95
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Uncertain
0.85
D
M_CAP
Pathogenic
0.84
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
MutationTaster
Benign
1.0
A
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-5.7
D
REVEL
Pathogenic
0.93
Sift
Benign
0.037
D
Sift4G
Uncertain
0.014
D
Vest4
0.89
MutPred
0.98
Gain of glycosylation at G1181 (P = 4e-04);
MVP
1.0
MPC
0.56
ClinPred
0.99
D
GERP RS
2.9
gMVP
1.0

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: rs72656330; hg19: chr17-48264274; API