7-94427288-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_000089.4(COL1A2):​c.3260G>T​(p.Gly1087Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1087D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

COL1A2
NM_000089.4 missense

Scores

15
3
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.76
Variant links:
Genes affected
COL1A2 (HGNC:2198): (collagen type I alpha 2 chain) This gene encodes the pro-alpha2 chain 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 VIIB, recessive Ehlers-Danlos syndrome Classical type, idiopathic osteoporosis, and atypical Marfan syndrome. Symptoms associated with mutations in this gene, however, tend to be less severe than mutations in the gene for the alpha1 chain of type I collagen (COL1A1) reflecting the different role of alpha2 chains in matrix integrity. Three 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 13 ACMG points.

PM1
In a compositionally_biased_region Pro residues (size 15) in uniprot entity CO1A2_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_000089.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL1A2. . Gene score misZ: 2.1491 (greater than the threshold 3.09). Trascript score misZ: 3.5344 (greater than threshold 3.09). The gene has 437 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. GenCC has associacion of the gene with Ehlers-Danlos/osteogenesis imperfecta syndrome, Ehlers-Danlos syndrome, cardiac valvular type, ehlers-danlos syndrome, arthrochalasia type, 2, Ehlers-Danlos syndrome, arthrochalasia type, osteogenesis imperfecta type 3, high bone mass osteogenesis imperfecta, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2, osteogenesis imperfecta type 4, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 7-94427288-G-T is Pathogenic according to our data. Variant chr7-94427288-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 456829.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-94427288-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL1A2NM_000089.4 linkc.3260G>T p.Gly1087Val missense_variant 48/52 ENST00000297268.11 NP_000080.2 P08123A0A0S2Z3H5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL1A2ENST00000297268.11 linkc.3260G>T p.Gly1087Val missense_variant 48/521 NM_000089.4 ENSP00000297268.6 P08123

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 20, 2017In summary, this variant is a novel missense change affecting a residue that is known to be critical for normal protein structure, stability, and function. This type of missense change is also highly enriched in affected individuals and expected to be pathogenic. However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL1A2, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL1A2-related disease. However, a different missense substitution at this codon (p.Gly1087Asp) has been reported in an individual affected with osteogenesis imperfecta type III (PMID: 16786509). This sequence change replaces glycine with valine at codon 1087 of the COL1A2 protein (p.Gly1087Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.90
D;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.9
H;.
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-8.1
D;.
REVEL
Pathogenic
0.98
Sift
Uncertain
0.0010
D;.
Sift4G
Uncertain
0.041
D;D
Polyphen
1.0
D;.
Vest4
0.95
MutPred
1.0
Loss of relative solvent accessibility (P = 0.0676);.;
MVP
0.99
MPC
0.26
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.99
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
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

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

Other links and lift over

dbSNP: rs72659335; hg19: chr7-94056600; API