17-50188799-CAGAGAG-CAGAGAGAG

Variant names:

• chr17-50188799-C-CAG
• rs138425306
• NM_000088.4:c.3046-6_3046-5dupCT

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_000088.4(COL1A1):​c.3046-6_3046-5dupCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000536 in 1,515,564 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: COL1A1 NM_000088.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.14

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 17-50188799-C-CAG is Benign according to our data. Variant chr17-50188799-C-CAG is described in ClinVar as [Benign]. Clinvar id is 456762.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.3046-6_3046-5dupCT		splice_region_variant, intron_variant	Intron 41 of 50	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.2848-6_2848-5dupCT		splice_region_variant, intron_variant	Intron 38 of 47		XP_011522643.1
COL1A1	XM_005257058.5	c.2776-6_2776-5dupCT		splice_region_variant, intron_variant	Intron 39 of 48		XP_005257115.2
COL1A1	XM_005257059.5	c.2128-6_2128-5dupCT		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_3046-4insCT		splice_region_variant, intron_variant	Intron 41 of 50	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000486572.1	n.-246_-245insCT		upstream_gene_variant		3
COL1A1	ENST00000511732.1	n.-16_-15insCT		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.000113 AC: 17 AN: 149902 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000665

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000164

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000583 AC: 796 AN: 1365576 Hom.: 0 Cov.: 0 AF XY: 0.000576 AC XY: 392 AN XY: 680756

Gnomad4 AFR exome AF: 0.000826

Gnomad4 AMR exome AF: 0.000280

Gnomad4 ASJ exome AF: 0.000164

Gnomad4 EAS exome AF: 0.0000817

Gnomad4 SAS exome AF: 0.000191

Gnomad4 FIN exome AF: 0.0000798

Gnomad4 NFE exome AF: 0.000678

Gnomad4 OTH exome AF: 0.000498

GnomAD4 genome AF: 0.000113 AC: 17 AN: 149988 Hom.: 0 Cov.: 32 AF XY: 0.0000683 AC XY: 5 AN XY: 73260

Gnomad4 AFR AF: 0.000122

Gnomad4 AMR AF: 0.0000664

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000164

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

COL1A1-related disorder Benign:1

Mar 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs138425306; hg19: chr17-48266160;