rs72656356

Variant names:

• chr7-94401620-G-A
• rs72656356
• NM_000089.4:c.279G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_000089.4(COL1A2):​c.279G>A​(p.Met93Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000664 in 150,644 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M93T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: COL1A2 NM_000089.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.98
• Publications: 2 publications found

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]

COL1A2 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, arthrochalasia type, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• osteogenesis imperfecta

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• osteogenesis imperfecta type 1

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• osteogenesis imperfecta type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Ehlers-Danlos syndrome, arthrochalasia type

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• Ehlers-Danlos syndrome, cardiac valvular type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, PanelApp Australia, Orphanet, G2P
• combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen, Ambry Genetics
• Ehlers-Danlos/osteogenesis imperfecta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• high bone mass osteogenesis imperfecta

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000089.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the COL1A2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 437 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 2.1491 (below the threshold of 3.09). Trascript score misZ: 3.5344 (above the threshold of 3.09). GenCC associations: The gene is linked to osteogenesis imperfecta, osteogenesis imperfecta type 1, osteogenesis imperfecta type 4, Ehlers-Danlos syndrome, cardiac valvular type, Ehlers-Danlos syndrome, arthrochalasia type, 2, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2, Ehlers-Danlos syndrome, arthrochalasia type, osteogenesis imperfecta type 3, osteogenesis imperfecta type 2, high bone mass osteogenesis imperfecta, Ehlers-Danlos/osteogenesis imperfecta syndrome.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 7-94401620-G-A is Pathogenic according to our data. Variant chr7-94401620-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 456826.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.279G>A	p.Met93Ile	missense_variant, splice_region_variant	Exon 6 of 52	ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.279G>A	p.Met93Ile	missense_variant, splice_region_variant	Exon 6 of 52	1	NM_000089.4	ENSP00000297268.6

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150644 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000996

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150644 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73464

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41054

American (AMR) AF: 0.00 AC: 0 AN: 15132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.0000996 AC: 1 AN: 10036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67722

Other (OTH) AF: 0.00 AC: 0 AN: 2068

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, arthrochalasia type, 2 Pathogenic:1

Oct 05, 1989

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Pathogenic:1

Jun 07, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine with isoleucine at codon 93 of the COL1A2 protein (p.Met93Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant also falls at the last nucleotide of exon 6 of the COL1A2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature to have arisen de novo in one individual affected with Ehlers-Danlos syndrome (PMID: 2777808). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant causes an aberrant splicing in the mRNA leading to a protein lacking exon 6 in part of the protein products (PMID: 2777808). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	0.28	N;.
PhyloP100		6.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N;.
REVEL	Uncertain	0.50
Sift	Benign	0.14	T;.
Sift4G	Benign	0.20	T;T
Polyphen		0.21	B;.
Vest4		0.42
MutPred		0.50		Gain of sheet (P = 0.0221);.;
MVP		0.69
MPC		0.29
ClinPred		0.84	D
GERP RS		5.5
Varity_R		0.24
gMVP		0.76
Mutation Taster		=26/74	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72656356; hg19: chr7-94030932;