17-50184475-CAAAAAAA-CAAAAAAAAAA

Variant names:

• chr17-50184475-C-CAAA
• rs58879635
• NM_000088.4:c.*1024_*1026dupTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000088.4(COL1A1):​c.*1024_*1026dupTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 122,084 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00098 (0 hom.)
• Consequence: COL1A1 NM_000088.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.156
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.*1024_*1026dupTTT		3_prime_UTR_variant	Exon 51 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.*1024_*1026dupTTT		3_prime_UTR_variant	Exon 48 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.*1024_*1026dupTTT		3_prime_UTR_variant	Exon 49 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.*1024_*1026dupTTT		3_prime_UTR_variant	Exon 38 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.*1024_*1026dupTTT		3_prime_UTR_variant	Exon 51 of 51	1	NM_000088.4	ENSP00000225964.6

Frequencies

GnomAD3 genomes AF: 0.0000274 AC: 2 AN: 73078 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000477

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000160

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000979 AC: 48 AN: 49006 Hom.: 0 Cov.: 0 AF XY: 0.00106 AC XY: 24 AN XY: 22730

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

African (AFR) AF: 0.00273 AC: 6 AN: 2196

American (AMR) AF: 0.00 AC: 0 AN: 1332

Ashkenazi Jewish (ASJ) AF: 0.000955 AC: 3 AN: 3140

East Asian (EAS) AF: 0.000130 AC: 1 AN: 7700

South Asian (SAS) AF: 0.00 AC: 0 AN: 438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 64

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.00121 AC: 36 AN: 29864

Other (OTH) AF: 0.000504 AC: 2 AN: 3972

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000274 AC: 2 AN: 73078 Hom.: 0 Cov.: 26 AF XY: 0.0000576 AC XY: 2 AN XY: 34750

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

African (AFR) AF: 0.0000476 AC: 1 AN: 21022

American (AMR) AF: 0.000160 AC: 1 AN: 6268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1706

East Asian (EAS) AF: 0.00 AC: 0 AN: 2678

South Asian (SAS) AF: 0.00 AC: 0 AN: 2158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 120

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 34360

Other (OTH) AF: 0.00 AC: 0 AN: 898

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16

Splicing

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

Other links and lift over

dbSNP: rs58879635; hg19: chr17-48261836;