chr17-50184473-CACA-C

Variant names:

• chr17-50184473-CACA-C
• rs751268781
• NM_000088.4:c.*1026_*1028delTGT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000088.4(COL1A1):​c.*1026_*1028delTGT 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
• Publications: 1 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 -9 ACMG points.

• BP6: Variant 17-50184473-CACA-C is Benign according to our data. Variant chr17-50184473-CACA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 324065.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=1}.
• 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 rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.*1026_*1028delTGT		3_prime_UTR_variant	Exon 51 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.*1026_*1028delTGT		3_prime_UTR_variant	Exon 48 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.*1026_*1028delTGT		3_prime_UTR_variant	Exon 49 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.*1026_*1028delTGT		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.*1026_*1028delTGT		3_prime_UTR_variant	Exon 51 of 51	1	NM_000088.4	ENSP00000225964.6

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

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

African (AFR) AF: 0.00246 AC: 7 AN: 2850

American (AMR) AF: 0.0477 AC: 90 AN: 1886

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 77 AN: 3928

East Asian (EAS) AF: 0.0217 AC: 216 AN: 9944

South Asian (SAS) AF: 0.0145 AC: 8 AN: 552

European-Finnish (FIN) AF: 0.00641 AC: 1 AN: 156

Middle Eastern (MID) AF: 0.00260 AC: 1 AN: 384

European-Non Finnish (NFE) AF: 0.0245 AC: 939 AN: 38400

Other (OTH) AF: 0.0244 AC: 125 AN: 5120

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

African (AFR) AF: 0.0100 AC: 260 AN: 26012

American (AMR) AF: 0.0922 AC: 1011 AN: 10970

Ashkenazi Jewish (ASJ) AF: 0.0374 AC: 107 AN: 2860

East Asian (EAS) AF: 0.0142 AC: 63 AN: 4432

South Asian (SAS) AF: 0.0267 AC: 97 AN: 3628

European-Finnish (FIN) AF: 0.0477 AC: 268 AN: 5614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 182

European-Non Finnish (NFE) AF: 0.0450 AC: 2378 AN: 52828

Other (OTH) AF: 0.0349 AC: 52 AN: 1490

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis Imperfecta, Dominant Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Infantile cortical hyperostosis Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 20, 2021

GeneDx

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		0.51
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs751268781; hg19: chr17-48261834;