chr17-50196948-T-C

Variant names:

• chr17-50196948-T-C
• rs2075554
• NM_000088.4:c.804+62A>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.804+62A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.841 in 1,573,952 control chromosomes in the GnomAD database, including 560,575 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50025 hom., cov: 32)
  • Exomes 𝑓: 0.85 (510550 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.52
• Publications: 19 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=-0.91).
• BP6: Variant 17-50196948-T-C is Benign according to our data. Variant chr17-50196948-T-C is described in ClinVar as Benign. ClinVar VariationId is 674976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000088.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	NM_000088.4	MANE Select	c.804+62A>G		intron	N/A	NP_000079.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	ENST00000225964.10	TSL:1 MANE Select	c.804+62A>G		intron	N/A	ENSP00000225964.6
	COL1A1	ENST00000495677.1	TSL:3	n.531+62A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.808 AC: 122831 AN: 152032 Hom.: 50001 Cov.: 32

Gnomad AFR AF: 0.733

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.856

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.738

Gnomad FIN AF: 0.890

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.865

Gnomad OTH AF: 0.802

GnomAD4 exome AF: 0.845 AC: 1201428 AN: 1421802 Hom.: 510550 AF XY: 0.842 AC XY: 597642 AN XY: 709766

African (AFR) AF: 0.732 AC: 23886 AN: 32642

American (AMR) AF: 0.710 AC: 31443 AN: 44296

Ashkenazi Jewish (ASJ) AF: 0.851 AC: 22015 AN: 25858

East Asian (EAS) AF: 0.631 AC: 24900 AN: 39456

South Asian (SAS) AF: 0.733 AC: 62527 AN: 85294

European-Finnish (FIN) AF: 0.876 AC: 46709 AN: 53336

Middle Eastern (MID) AF: 0.819 AC: 4095 AN: 4998

European-Non Finnish (NFE) AF: 0.870 AC: 936560 AN: 1076996

Other (OTH) AF: 0.837 AC: 49293 AN: 58926

GnomAD4 genome AF: 0.808 AC: 122907 AN: 152150 Hom.: 50025 Cov.: 32 AF XY: 0.805 AC XY: 59843 AN XY: 74376

African (AFR) AF: 0.733 AC: 30402 AN: 41490

American (AMR) AF: 0.751 AC: 11465 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.856 AC: 2972 AN: 3472

East Asian (EAS) AF: 0.672 AC: 3471 AN: 5166

South Asian (SAS) AF: 0.738 AC: 3555 AN: 4816

European-Finnish (FIN) AF: 0.890 AC: 9440 AN: 10608

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.865 AC: 58832 AN: 68002

Other (OTH) AF: 0.800 AC: 1691 AN: 2114

Alfa AF: 0.845 Hom.: 26151

Bravo AF: 0.794

Asia WGS AF: 0.689 AC: 2400 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.1
DANN	Benign	0.53
PhyloP100		-1.5
Mutation Taster		=21/79	disease causing

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: rs2075554; hg19: chr17-48274309; COSMIC: COSV56809294; COSMIC: COSV56809294;