rs139528613

chr7-94399074-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS1

The NM_000089.4(COL1A2):c.122G>A(p.Arg41His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000521 in 1,613,620 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R41C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: COL1A2 NM_000089.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.92

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 Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL1A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.012681812).
• BP6: Variant 7-94399074-G-A is Benign according to our data. Variant chr7-94399074-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 360944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00288 (438/152200) while in subpopulation AFR AF= 0.0102 (425/41556). AF 95% confidence interval is 0.00942. There are 1 homozygotes in gnomad4. There are 197 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A2	NM_000089.4	c.122G>A	p.Arg41His	missense_variant	4/52	ENST00000297268.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A2	ENST00000297268.11	c.122G>A	p.Arg41His	missense_variant	4/52	1	NM_000089.4	P1

Frequencies

GnomAD3 genomes AF: 0.00288 AC: 438 AN: 152082 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.000764 AC: 192 AN: 251424 Hom.: 0 AF XY: 0.000574 AC XY: 78 AN XY: 135890

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000275 AC: 402 AN: 1461420 Hom.: 0 Cov.: 30 AF XY: 0.000245 AC XY: 178 AN XY: 727016

Gnomad4 AFR exome AF: 0.00983

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.00288 AC: 438 AN: 152200 Hom.: 1 Cov.: 32 AF XY: 0.00265 AC XY: 197 AN XY: 74422

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.000453 Hom.: 0

Bravo AF: 0.00326

ESP6500AA AF: 0.0123 AC: 54

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000873 AC: 106

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2016	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. -

Osteogenesis imperfecta Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Aug 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

COL1A2-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 21, 2017

The p.Arg41His variant (rs139528613) was reported as identified by whole exome sequencing in three African-American mothers with premature ruptures of membranes (Modi 2017). However, the p.Arg41His variant has been identified with allele frequency of 1.0 percent (on 242 out of 24,024 chromosomes) in African populations and with an overall population frequency of 0.09 percent (identified on 258 out of 277,154 chromosomes) and in gnomAD browser. Additionally, the p.Arg41His variant is also listed in the ClinVar database with current classification of benign or likely benign (Variation ID 360944). -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2020

This alteration is classified as 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	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.97	D;D
MetaRNN	Benign	0.013	T;T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	D;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.026	D;.
Sift4G	Uncertain	0.035	D;D
Polyphen		0.99	D;.
Vest4		0.39
MVP		0.69
MPC		0.32
ClinPred		0.030	T
GERP RS		5.8
Varity_R		0.12
gMVP		0.32

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: rs139528613; hg19: chr7-94028386;