rs878912123

Variant names:

• chr17-50184474-AC-A
• rs878912123
• NM_000088.4:c.*1027delG

Variant summary

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

The NM_000088.4(COL1A1):​c.*1027delG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. 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 0.000042 (0 hom., cov: 12)
  • Exomes 𝑓: 0.00015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL1A1 NM_000088.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 0.490
• 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: 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.*1027delG		3_prime_UTR_variant	Exon 51 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.*1027delG		3_prime_UTR_variant	Exon 48 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.*1027delG		3_prime_UTR_variant	Exon 49 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.*1027delG		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.*1027delG		3_prime_UTR_variant	Exon 51 of 51	1	NM_000088.4	ENSP00000225964.6

Frequencies

GnomAD3 genomes AF: 0.0000417 AC: 5 AN: 119876 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.0000622

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000886

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000184

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000150 AC: 10 AN: 66758 Hom.: 0 Cov.: 0 AF XY: 0.000129 AC XY: 4 AN XY: 30952

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

African (AFR) AF: 0.00 AC: 0 AN: 3306

American (AMR) AF: 0.00 AC: 0 AN: 1856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4252

East Asian (EAS) AF: 0.00 AC: 0 AN: 10098

South Asian (SAS) AF: 0.00 AC: 0 AN: 568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 426

European-Non Finnish (NFE) AF: 0.000148 AC: 6 AN: 40562

Other (OTH) AF: 0.000724 AC: 4 AN: 5524

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000417 AC: 5 AN: 119926 Hom.: 0 Cov.: 12 AF XY: 0.0000515 AC XY: 3 AN XY: 58228

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

African (AFR) AF: 0.0000620 AC: 2 AN: 32236

American (AMR) AF: 0.0000885 AC: 1 AN: 11298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2904

East Asian (EAS) AF: 0.00 AC: 0 AN: 4732

South Asian (SAS) AF: 0.00 AC: 0 AN: 3838

European-Finnish (FIN) AF: 0.000129 AC: 1 AN: 7766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.0000184 AC: 1 AN: 54458

Other (OTH) AF: 0.00 AC: 0 AN: 1678

⚠️ 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.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs878912123; hg19: chr17-48261835;