rs139851311

Variant names:

• chr7-94427672-G-A
• rs139851311
• NM_000089.4:c.3313G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 3P and 11B. PM1 PP2 BP4_Moderate BP6 BS1 BS2

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:3 B:9
• Conservation: PhyloP100: 8.14
• Publications: 7 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):

• COL1A2-related Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• COL1A2-related osteogenesis imperfecta

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Ehlers-Danlos syndrome, arthrochalasia type, 2

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

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

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

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

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

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

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000089.4
• 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.
• 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 VariationId is 360968.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 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 GnomAdExome4. There are 950 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000089.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A2	NM_000089.4	MANE Select	c.3313G>A	p.Gly1105Ser	missense	Exon 49 of 52	NP_000080.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A2	ENST00000297268.11	TSL:1 MANE Select	c.3313G>A	p.Gly1105Ser	missense	Exon 49 of 52	ENSP00000297268.6	P08123
	COL1A2	ENST00000959377.1		c.3310G>A	p.Gly1104Ser	missense	Exon 49 of 52	ENSP00000629436.1
	COL1A2	ENST00000959379.1		c.3313G>A	p.Gly1105Ser	missense	Exon 49 of 52	ENSP00000629438.1

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

GnomAD2 exomes AF: 0.000995 AC: 250 AN: 251270 AF XY: 0.00101

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 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

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.00190 AC: 85 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000705 AC: 28 AN: 39696

South Asian (SAS) AF: 0.00288 AC: 248 AN: 86258

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00125 AC: 1392 AN: 1111994

Other (OTH) AF: 0.00139 AC: 84 AN: 60396

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

African (AFR) AF: 0.000409 AC: 17 AN: 41530

American (AMR) AF: 0.00183 AC: 28 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68016

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.000956 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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (2)
-	-	2	Osteogenesis imperfecta (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Connective tissue disorder (1)
-	1	-	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome, arthrochalasia type, 2 (1)
-	-	1	Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.13	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.78
Sift	Benign	0.18	T
Sift4G	Benign	0.17	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
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs139851311; hg19: chr7-94056984; COSMIC: COSV106098388; COSMIC: COSV106098388;