rs11079898

Variant names:

• chr17-50197263-T-C
• rs11079898
• NM_000088.4:c.697-30A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000088.4(COL1A1):​c.697-30A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0392 in 1,610,468 control chromosomes in the GnomAD database, including 5,606 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2652 hom., cov: 32)
  • Exomes 𝑓: 0.031 (2954 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.41
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-50197263-T-C is Benign according to our data. Variant chr17-50197263-T-C is described in ClinVar as Benign. ClinVar VariationId is 675133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.697-30A>G		intron_variant	Intron 9 of 50	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.697-30A>G		intron_variant	Intron 9 of 47		XP_011522643.1
COL1A1	XM_005257058.5	c.697-30A>G		intron_variant	Intron 9 of 48		XP_005257115.2
COL1A1	XM_005257059.5	c.697-30A>G		intron_variant	Intron 9 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.697-30A>G		intron_variant	Intron 9 of 50	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000495677.1	n.424-30A>G		intron_variant	Intron 4 of 7	3

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17480 AN: 151958 Hom.: 2639 Cov.: 32

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0480

Gnomad ASJ AF: 0.0276

Gnomad EAS AF: 0.00944

Gnomad SAS AF: 0.0567

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0837

GnomAD2 exomes AF: 0.0481 AC: 12063 AN: 250750 AF XY: 0.0436

Gnomad AFR exome AF: 0.360

Gnomad AMR exome AF: 0.0277

Gnomad ASJ exome AF: 0.0223

Gnomad EAS exome AF: 0.00615

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0351

GnomAD4 exome AF: 0.0312 AC: 45572 AN: 1458392 Hom.: 2954 Cov.: 33 AF XY: 0.0314 AC XY: 22763 AN XY: 725658

African (AFR) AF: 0.365 AC: 12178 AN: 33382

American (AMR) AF: 0.0297 AC: 1329 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0217 AC: 566 AN: 26124

East Asian (EAS) AF: 0.00640 AC: 254 AN: 39692

South Asian (SAS) AF: 0.0595 AC: 5124 AN: 86140

European-Finnish (FIN) AF: 0.0148 AC: 788 AN: 53330

Middle Eastern (MID) AF: 0.0571 AC: 240 AN: 4202

European-Non Finnish (NFE) AF: 0.0201 AC: 22334 AN: 1110656

Other (OTH) AF: 0.0459 AC: 2759 AN: 60156

GnomAD4 genome AF: 0.115 AC: 17522 AN: 152076 Hom.: 2652 Cov.: 32 AF XY: 0.112 AC XY: 8344 AN XY: 74336

African (AFR) AF: 0.352 AC: 14596 AN: 41420

American (AMR) AF: 0.0478 AC: 731 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 96 AN: 3472

East Asian (EAS) AF: 0.00927 AC: 48 AN: 5178

South Asian (SAS) AF: 0.0563 AC: 271 AN: 4812

European-Finnish (FIN) AF: 0.0130 AC: 138 AN: 10604

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0212 AC: 1444 AN: 67994

Other (OTH) AF: 0.0828 AC: 175 AN: 2114

Alfa AF: 0.122 Hom.: 1605

Bravo AF: 0.127

Asia WGS AF: 0.0520 AC: 180 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.49
DANN	Benign	0.33
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs11079898; hg19: chr17-48274624; COSMIC: COSV56806377;