chr17-50196103-T-C

Variant names:

• chr17-50196103-T-C
• rs2141279
• NM_000088.4:c.1002+52A>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.1002+52A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.843 in 1,612,242 control chromosomes in the GnomAD database, including 574,960 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (57149 hom., cov: 32)
  • Exomes 𝑓: 0.84 (517811 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.472
• Publications: 11 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=-0.85).
• BP6: Variant 17-50196103-T-C is Benign according to our data. Variant chr17-50196103-T-C is described in ClinVar as Benign. ClinVar VariationId is 674801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.934 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.1002+52A>G		intron_variant	Intron 15 of 50	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.957+211A>G		intron_variant	Intron 14 of 47		XP_011522643.1
COL1A1	XM_005257058.5	c.1002+52A>G		intron_variant	Intron 15 of 48		XP_005257115.2
COL1A1	XM_005257059.5	c.957+211A>G		intron_variant	Intron 14 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.1002+52A>G		intron_variant	Intron 15 of 50	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000485870.1	n.379A>G		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.864 AC: 131442 AN: 152070 Hom.: 57106 Cov.: 32

Gnomad AFR AF: 0.942

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.833

Gnomad ASJ AF: 0.899

Gnomad EAS AF: 0.709

Gnomad SAS AF: 0.801

Gnomad FIN AF: 0.812

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.847

Gnomad OTH AF: 0.860

GnomAD4 exome AF: 0.841 AC: 1228225 AN: 1460054 Hom.: 517811 Cov.: 37 AF XY: 0.841 AC XY: 610763 AN XY: 726400

African (AFR) AF: 0.949 AC: 31726 AN: 33448

American (AMR) AF: 0.805 AC: 35953 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.919 AC: 24014 AN: 26124

East Asian (EAS) AF: 0.689 AC: 27340 AN: 39672

South Asian (SAS) AF: 0.818 AC: 70493 AN: 86214

European-Finnish (FIN) AF: 0.813 AC: 43358 AN: 53356

Middle Eastern (MID) AF: 0.887 AC: 5114 AN: 5764

European-Non Finnish (NFE) AF: 0.846 AC: 939303 AN: 1110486

Other (OTH) AF: 0.844 AC: 50924 AN: 60320

GnomAD4 genome AF: 0.864 AC: 131542 AN: 152188 Hom.: 57149 Cov.: 32 AF XY: 0.861 AC XY: 64012 AN XY: 74380

African (AFR) AF: 0.942 AC: 39097 AN: 41526

American (AMR) AF: 0.833 AC: 12746 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.899 AC: 3121 AN: 3470

East Asian (EAS) AF: 0.709 AC: 3665 AN: 5170

South Asian (SAS) AF: 0.800 AC: 3861 AN: 4824

European-Finnish (FIN) AF: 0.812 AC: 8612 AN: 10610

Middle Eastern (MID) AF: 0.922 AC: 271 AN: 294

European-Non Finnish (NFE) AF: 0.847 AC: 57564 AN: 67970

Other (OTH) AF: 0.856 AC: 1804 AN: 2108

Alfa AF: 0.849 Hom.: 6850

Bravo AF: 0.871

Asia WGS AF: 0.733 AC: 2547 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	11
DANN	Benign	0.74
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2141279; hg19: chr17-48273464;