17-50191660-C-G

Variant names:

• chr17-50191660-C-G
• rs2075556
• NM_000088.4:c.2127+128G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000088.4(COL1A1):​c.2127+128G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,177,800 control chromosomes in the GnomAD database, including 14,586 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (1747 hom., cov: 33)
  • Exomes 𝑓: 0.15 (12839 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.221
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-50191660-C-G is Benign according to our data. Variant chr17-50191660-C-G is described in ClinVar as Benign. ClinVar VariationId is 1291104.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	NM_000088.4	MANE Select	c.2127+128G>C		intron	N/A	NP_000079.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	ENST00000225964.10	TSL:1 MANE Select	c.2127+128G>C		intron	N/A	ENSP00000225964.6
	COL1A1	ENST00000476387.1	TSL:2	n.476+128G>C		intron	N/A
	COL1A1	ENST00000504289.1	TSL:2	n.*206G>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22092 AN: 152098 Hom.: 1743 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.344

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.158

GnomAD4 exome AF: 0.149 AC: 152521 AN: 1025584 Hom.: 12839 Cov.: 14 AF XY: 0.153 AC XY: 79673 AN XY: 520722

African (AFR) AF: 0.124 AC: 3053 AN: 24648

American (AMR) AF: 0.153 AC: 5427 AN: 35470

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 3670 AN: 22612

East Asian (EAS) AF: 0.320 AC: 10959 AN: 34246

South Asian (SAS) AF: 0.248 AC: 17990 AN: 72420

European-Finnish (FIN) AF: 0.139 AC: 5926 AN: 42658

Middle Eastern (MID) AF: 0.166 AC: 591 AN: 3562

European-Non Finnish (NFE) AF: 0.131 AC: 97842 AN: 744192

Other (OTH) AF: 0.154 AC: 7063 AN: 45776

GnomAD4 genome AF: 0.145 AC: 22100 AN: 152216 Hom.: 1747 Cov.: 33 AF XY: 0.148 AC XY: 11020 AN XY: 74412

African (AFR) AF: 0.126 AC: 5240 AN: 41538

American (AMR) AF: 0.146 AC: 2233 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 561 AN: 3470

East Asian (EAS) AF: 0.344 AC: 1774 AN: 5164

South Asian (SAS) AF: 0.241 AC: 1164 AN: 4826

European-Finnish (FIN) AF: 0.133 AC: 1411 AN: 10614

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9294 AN: 67986

Other (OTH) AF: 0.161 AC: 339 AN: 2112

Alfa AF: 0.0701 Hom.: 69

Bravo AF: 0.143

Asia WGS AF: 0.294 AC: 1019 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.3
DANN	Benign	0.49
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

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: rs2075556; hg19: chr17-48269021; COSMIC: COSV56804431; COSMIC: COSV56804431;