NM_000088.4:c.3064G>A

Variant names:

• chr17-50188777-C-T
• rs66523073
• NM_000088.4:c.3064G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000088.4(COL1A1):​c.3064G>A​(p.Gly1022Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1022C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.99
• Publications: 5 publications found

Genes affected

COL1A1 (HGNC:2197): (collagen type I alpha 1 chain) This gene encodes the pro-alpha1 chains 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 VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. Reciprocal translocations between chromosomes 17 and 22, where this gene and the gene for platelet-derived growth factor beta are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans, resulting from unregulated expression of the growth factor. Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]

COL1A1 Gene-Disease associations (from GenCC):

• Caffey disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1

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

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, arthrochalasia type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• 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, ClinGen
• 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: G2P, Orphanet, ClinGen
• Ehlers-Danlos syndrome, classic type, 1

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 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 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000088.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-50188776-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 499457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the COL1A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 368 curated pathogenic missense variants (we use a threshold of 10). The gene has 98 curated benign missense variants. Gene score misZ: 3.5319 (above the threshold of 3.09). Trascript score misZ: 5.7733 (above the threshold of 3.09). GenCC associations: The gene is linked to high bone mass osteogenesis imperfecta, Ehlers-Danlos syndrome, arthrochalasia type, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, Caffey disease, osteogenesis imperfecta type 4, osteogenesis imperfecta type 3, Ehlers-Danlos syndrome, classic type, Ehlers-Danlos syndrome, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1, Ehlers-Danlos syndrome, classic type, 1, Ehlers-Danlos/osteogenesis imperfecta syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 17-50188777-C-T is Pathogenic according to our data. Variant chr17-50188777-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17296.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.3064G>A	p.Gly1022Ser	missense_variant	Exon 42 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.2866G>A	p.Gly956Ser	missense_variant	Exon 39 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.2794G>A	p.Gly932Ser	missense_variant	Exon 40 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.2146G>A	p.Gly716Ser	missense_variant	Exon 29 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.3064G>A	p.Gly1022Ser	missense_variant	Exon 42 of 51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000511732.1	n.8G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
COL1A1	ENST00000486572.1	n.-223G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type III Pathogenic:1

Nov 25, 1989

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

COL1A1-related disorder Pathogenic:1

Jun 07, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COL1A1 c.3064G>A variant is predicted to result in the amino acid substitution p.Gly1022Ser. This variant has been reported in several individuals with osteogenesis imperfecta (Reported as Gly844Ser in Pack et al 1989. PubMed ID: 2511192; Chen CP et al 2012. PubMed ID: 23072183; Supp. Table 1, Patient PUMC-208 in Li L et al 2019. PubMed ID: 30715774). This variant is located in the conserved Gly-Xaa-Yaa triple helical domain where substitutions of a glycine are usually pathogenic (Residues 179-1192, https://www.uniprot.org/; Legacy nomenclature in Marini et al. 2007. PubMed ID: 17078022 indicates amino acids 1-1012; Symoens. 2014. PubMed ID: 25146735). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.98	D
PhyloP100		5.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Vest4		0.88
MutPred		0.99		Gain of phosphorylation at G1022 (P = 0.0039);
MVP		0.99
MPC		0.56
ClinPred		1.0	D
GERP RS		4.0
gMVP		1.0
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs66523073; hg19: chr17-48266138;