rs139851311

chr7-94427672-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM1 PP2 BP4_Moderate BP6 BS1

The NM_000089.4(COL1A2):c.3313G>A(p.Gly1105Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,614,106 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: COL1A2 NM_000089.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:7
• Conservation: PhyloP100: 8.14

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000089.4
• PP2: Missense variant where missense usually causes diseases, COL1A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.12622899).
• BP6: Variant 7-94427672-G-A is Benign according to our data. Variant chr7-94427672-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 360968.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=7}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00127 (1857/1461870) while in subpopulation SAS AF= 0.00288 (248/86258). AF 95% confidence interval is 0.00258. There are 5 homozygotes in gnomad4_exome. There are 950 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A2	NM_000089.4	c.3313G>A	p.Gly1105Ser	missense_variant	49/52	ENST00000297268.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A2	ENST00000297268.11	c.3313G>A	p.Gly1105Ser	missense_variant	49/52	1	NM_000089.4	P1
COL1A2	ENST00000464916.1	n.361G>A		non_coding_transcript_exon_variant	1/4	2
COL1A2	ENST00000481570.5	n.4094G>A		non_coding_transcript_exon_variant	6/8	2

Frequencies

GnomAD3 genomes AF: 0.000717 AC: 109 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000995 AC: 250 AN: 251270 Hom.: 0 AF XY: 0.00101 AC XY: 137 AN XY: 135800

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.00238

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000784

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00127 AC: 1857 AN: 1461870 Hom.: 5 Cov.: 33 AF XY: 0.00131 AC XY: 950 AN XY: 727238

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000705

Gnomad4 SAS exome AF: 0.00288

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00125

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000739 AC XY: 55 AN XY: 74436

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000890 Hom.: 1

Bravo AF: 0.000899

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000972 AC: 118

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	The COL1A2 c.3313G>A; p.Gly1105Ser variant (rs139851311) is reported in the literature in several individuals affected with osteogenesis imperfecta or Ehlers-Danlos Syndrome, though it was not demonstrated to cause disease (Junkiert-Czarnecka 2022, Mei 2022, Stephen 2014, Zhang 2012). This variant is also reported in ClinVar (Variation ID: 360968). It is found in the South Asian population with an overall allele frequency of 0.24% (73/30610 alleles) in the Genome Aggregation Database. The glycine at codon 1105 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.783). It is unclear if this glycine residue is incorporated into the collagen triple helix domain. While the population frequency of this variant is inconsistent with disease, given the lack of clinical and functional data, the significance of the p.Gly1105Ser variant is uncertain at this time. References: Junkiert-Czarnecka A et al. Next-Generation Sequencing of Connective Tissue Genes in Patients with Classical Ehlers-Danlos Syndrome. Curr Issues Mol Biol. 2022 Mar 25;44(4):1472-1478. PMID: 35723357. 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. Stephen J et al. Mutation spectrum of COL1A1 and COL1A2 genes in Indian patients with osteogenesis imperfecta. Am J Med Genet A. 2014 Jun;164A(6):1482-9. PMID: 24668929. Zhang ZL et al. The identification of novel mutations in COL1A1, COL1A2, and LEPRE1 genes in Chinese patients with osteogenesis imperfecta. J Bone Miner Metab. 2012 Jan;30(1):69-77. PMID: 21667357. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 06, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	- -

Osteogenesis imperfecta Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Dec 01, 2019	- -

Ehlers-Danlos syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 10, 2021

- -

Connective tissue disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 23, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Ehlers-danlos syndrome, arthrochalasia type, 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 05, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Uncertain	23
Dann	Benign	0.90
DEOGEN2	Uncertain	0.66	D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.73	T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.4	D;.
REVEL	Pathogenic	0.78
Sift	Benign	0.18	T;.
Sift4G	Benign	0.17	T;T
Polyphen		1.0	D;.
Vest4		0.87
MVP		0.95
MPC		0.21
ClinPred		0.048	T
GERP RS		5.8
Varity_R		0.72
gMVP		0.91

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

Other links and lift over

dbSNP: rs139851311; hg19: chr7-94056984;