17-50197964-G-A

Variant names:

• chr17-50197964-G-A
• rs201136122
• NM_000088.4:c.627C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BP6 BS2

The NM_000088.4(COL1A1):​c.627C>T​(p.Gly209Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,613,866 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G209G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00049 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (2 hom.)
• Consequence: COL1A1 NM_000088.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: -0.330
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
• COL1A1-related Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1

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

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

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• osteogenesis imperfecta

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• 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
• 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, G2P, Orphanet
• 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: Likely_benign. The variant received -4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 17-50197964-G-A is Benign according to our data. Variant chr17-50197964-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 324117.
• BS2: High AC in GnomAd4 at 75 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000088.4. 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
	COL1A1	NM_000088.4	MANE Select	c.627C>T	p.Gly209Gly	synonymous	Exon 8 of 51	NP_000079.2	P02452

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	ENST00000225964.10	TSL:1 MANE Select	c.627C>T	p.Gly209Gly	synonymous	Exon 8 of 51	ENSP00000225964.6	P02452
	COL1A1	ENST00000861334.1		c.627C>T	p.Gly209Gly	synonymous	Exon 8 of 51	ENSP00000531393.1
	COL1A1	ENST00000861339.1		c.627C>T	p.Gly209Gly	synonymous	Exon 8 of 51	ENSP00000531398.1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 151996 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000431 AC: 108 AN: 250318 AF XY: 0.000405

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00597

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.000197 AC: 288 AN: 1461752 Hom.: 2 Cov.: 32 AF XY: 0.000198 AC XY: 144 AN XY: 727178

African (AFR) AF: 0.0000598 AC: 2 AN: 33468

American (AMR) AF: 0.000805 AC: 36 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00647 AC: 169 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

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

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1111944

Other (OTH) AF: 0.000497 AC: 30 AN: 60384

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152114 Hom.: 1 Cov.: 32 AF XY: 0.000659 AC XY: 49 AN XY: 74362

African (AFR) AF: 0.0000241 AC: 1 AN: 41482

American (AMR) AF: 0.00262 AC: 40 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67976

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000592 Hom.: 0

Bravo AF: 0.000544

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome, arthrochalasia type (1)
-	1	-	Infantile cortical hyperostosis (1)
-	-	1	Osteogenesis imperfecta (1)
-	-	1	Osteogenesis imperfecta type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.69
PhyloP100		-0.33
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.54		Position offset: 2

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

Other links and lift over

dbSNP: rs201136122; hg19: chr17-48275325; COSMIC: COSV56809613; COSMIC: COSV56809613;