NM_000088.4:c.3046-6_3046-5dupCT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong 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 Likely 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/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 -12 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/Likely_benign. ClinVar VariationId is 456762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 17 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.3046-6_3046-5dupCT		splice_region intron	N/A	NP_000079.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	ENST00000225964.10	TSL:1 MANE Select	c.3046-5_3046-4insCT		splice_region intron	N/A	ENSP00000225964.6
	COL1A1	ENST00000861334.1		c.3046-5_3046-4insCT		splice_region intron	N/A	ENSP00000531393.1
	COL1A1	ENST00000861339.1		c.3046-5_3046-4insCT		splice_region intron	N/A	ENSP00000531398.1

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

GnomAD2 exomes AF: 0.000939 AC: 66 AN: 70316 AF XY: 0.00121

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.000620

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000297

Gnomad NFE exome AF: 0.00119

Gnomad OTH exome AF: 0.00144

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

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

African (AFR) AF: 0.000826 AC: 26 AN: 31484

American (AMR) AF: 0.000280 AC: 12 AN: 42902

Ashkenazi Jewish (ASJ) AF: 0.000164 AC: 4 AN: 24410

East Asian (EAS) AF: 0.0000817 AC: 3 AN: 36718

South Asian (SAS) AF: 0.000191 AC: 16 AN: 83934

European-Finnish (FIN) AF: 0.0000798 AC: 4 AN: 50096

Middle Eastern (MID) AF: 0.000366 AC: 2 AN: 5460

European-Non Finnish (NFE) AF: 0.000678 AC: 701 AN: 1034358

Other (OTH) AF: 0.000498 AC: 28 AN: 56214

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

African (AFR) AF: 0.000122 AC: 5 AN: 41140

American (AMR) AF: 0.0000664 AC: 1 AN: 15052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000164 AC: 11 AN: 67244

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.000293 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	COL1A1-related disorder (1)
-	-	1	not specified (1)
-	-	1	Osteogenesis imperfecta type I (1)

Computational scores

Source: dbNSFP v4.9

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;