chr17-50188799-C-CAGAG

Variant names:

• chr17-50188799-C-CAGAG
• rs138425306
• NM_000088.4:c.3046-8_3046-5dupCTCT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000088.4(COL1A1):​c.3046-8_3046-5dupCTCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 1,539,044 control chromosomes in the GnomAD database, including 59 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (8 hom.)
• Consequence: COL1A1 NM_000088.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.14
• Publications: 6 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 -16 ACMG points.

• BP6: Variant 17-50188799-C-CAGAG is Benign according to our data. Variant chr17-50188799-C-CAGAG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 456763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.3046-8_3046-5dupCTCT		splice_region_variant, intron_variant	Intron 41 of 50	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.2848-8_2848-5dupCTCT		splice_region_variant, intron_variant	Intron 38 of 47		XP_011522643.1
COL1A1	XM_005257058.5	c.2776-8_2776-5dupCTCT		splice_region_variant, intron_variant	Intron 39 of 48		XP_005257115.2
COL1A1	XM_005257059.5	c.2128-8_2128-5dupCTCT		splice_region_variant, intron_variant	Intron 28 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.3046-5_3046-4insCTCT		splice_region_variant, intron_variant	Intron 41 of 50	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000486572.1	n.-246_-245insCTCT		upstream_gene_variant		3
COL1A1	ENST00000511732.1	n.-16_-15insCTCT		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2298 AN: 150008 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0535

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.000253

Gnomad OTH AF: 0.00922

GnomAD2 exomes AF: 0.0140 AC: 985 AN: 70316 AF XY: 0.0115

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.0222

Gnomad ASJ exome AF: 0.000620

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000917

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.00174 AC: 2423 AN: 1388950 Hom.: 8 Cov.: 0 AF XY: 0.00154 AC XY: 1065 AN XY: 691706

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0578 AC: 1846 AN: 31922

American (AMR) AF: 0.00381 AC: 164 AN: 43072

Ashkenazi Jewish (ASJ) AF: 0.0000811 AC: 2 AN: 24650

East Asian (EAS) AF: 0.00 AC: 0 AN: 37022

South Asian (SAS) AF: 0.0000592 AC: 5 AN: 84464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50374

Middle Eastern (MID) AF: 0.00616 AC: 34 AN: 5516

European-Non Finnish (NFE) AF: 0.000155 AC: 163 AN: 1054854

Other (OTH) AF: 0.00366 AC: 209 AN: 57076

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0153 AC: 2299 AN: 150094 Hom.: 51 Cov.: 32 AF XY: 0.0147 AC XY: 1076 AN XY: 73312

African (AFR) AF: 0.0534 AC: 2196 AN: 41160

American (AMR) AF: 0.00412 AC: 62 AN: 15062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9942

Middle Eastern (MID) AF: 0.0139 AC: 4 AN: 288

European-Non Finnish (NFE) AF: 0.000253 AC: 17 AN: 67278

Other (OTH) AF: 0.00915 AC: 19 AN: 2076

Alfa AF: 0.000953 Hom.: 0

Bravo AF: 0.0170

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Feb 06, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 10, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Apr 03, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta Benign:1

Feb 11, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome Benign:1

Apr 12, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

COL1A1-related disorder Benign:1

Mar 16, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Osteogenesis imperfecta type I Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs138425306; hg19: chr17-48266160;