17-50184473-CACA-C

Position:

• chr17-50184473-CACA-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_000088.4(COL1A1):​c.*1026_*1028del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0332 in 171,936 control chromosomes in the GnomAD database, including 97 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.039 (94 hom., cov: 12)
  • Exomes 𝑓: 0.023 (3 hom.)
• Consequence: COL1A1 NM_000088.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.507

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 Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0874 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.*1026_*1028del		3_prime_UTR_variant	51/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_005257058.5	c.*1026_*1028del		3_prime_UTR_variant	49/49		XP_005257115.2
COL1A1	XM_005257059.5	c.*1026_*1028del		3_prime_UTR_variant	38/38		XP_005257116.2
COL1A1	XM_011524341.2	c.*1026_*1028del		3_prime_UTR_variant	48/48		XP_011522643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.*1026_*1028del		3_prime_UTR_variant	51/51	1	NM_000088.4	ENSP00000225964	P1

Frequencies

GnomAD3 genomes AF: 0.0391 AC: 4246 AN: 108688 Hom.: 93 Cov.: 12

Gnomad AFR AF: 0.0100

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0920

Gnomad ASJ AF: 0.0374

Gnomad EAS AF: 0.0142

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.0477

Gnomad MID AF: 0.00532

Gnomad NFE AF: 0.0450

Gnomad OTH AF: 0.0345

GnomAD4 exome AF: 0.0232 AC: 1464 AN: 63220 Hom.: 3 AF XY: 0.0225 AC XY: 658 AN XY: 29194

Gnomad4 AFR exome AF: 0.00246

Gnomad4 AMR exome AF: 0.0477

Gnomad4 ASJ exome AF: 0.0196

Gnomad4 EAS exome AF: 0.0217

Gnomad4 SAS exome AF: 0.0145

Gnomad4 FIN exome AF: 0.00641

Gnomad4 NFE exome AF: 0.0245

Gnomad4 OTH exome AF: 0.0244

GnomAD4 genome AF: 0.0391 AC: 4246 AN: 108716 Hom.: 94 Cov.: 12 AF XY: 0.0397 AC XY: 2055 AN XY: 51728

Gnomad4 AFR AF: 0.0100

Gnomad4 AMR AF: 0.0922

Gnomad4 ASJ AF: 0.0374

Gnomad4 EAS AF: 0.0142

Gnomad4 SAS AF: 0.0267

Gnomad4 FIN AF: 0.0477

Gnomad4 NFE AF: 0.0450

Gnomad4 OTH AF: 0.0349

Alfa AF: 0.0339 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ehlers-Danlos syndrome type 7A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Osteogenesis Imperfecta, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Infantile cortical hyperostosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs751268781; hg19: chr17-48261834;