17-50196078-T-C

Variant names:

• chr17-50196078-T-C
• rs2734281
• NM_000088.4:c.1002+77A>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+77A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.826 in 1,606,640 control chromosomes in the GnomAD database, including 550,872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54671 hom., cov: 32)
  • Exomes 𝑓: 0.82 (496201 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.79
• Publications: 10 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
• COL1A1-related Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, Ambry Genetics
• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, arthrochalasia type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• osteogenesis imperfecta

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• osteogenesis imperfecta type 1

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• osteogenesis imperfecta type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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: ClinGen, G2P, Orphanet
• 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=-0.86).
• BP6: Variant 17-50196078-T-C is Benign according to our data. Variant chr17-50196078-T-C is described in ClinVar as Benign. ClinVar VariationId is 674978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	NM_000088.4	MANE Select	c.1002+77A>G		intron	N/A	NP_000079.2	P02452

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	ENST00000225964.10	TSL:1 MANE Select	c.1002+77A>G		intron	N/A	ENSP00000225964.6	P02452
	COL1A1	ENST00000861334.1		c.1002+77A>G		intron	N/A	ENSP00000531393.1
	COL1A1	ENST00000861339.1		c.1002+77A>G		intron	N/A	ENSP00000531398.1

Frequencies

GnomAD3 genomes AF: 0.844 AC: 128296 AN: 152002 Hom.: 54633 Cov.: 32

Gnomad AFR AF: 0.929

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.794

Gnomad ASJ AF: 0.897

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.763

Gnomad FIN AF: 0.804

Gnomad MID AF: 0.918

Gnomad NFE AF: 0.834

Gnomad OTH AF: 0.833

GnomAD4 exome AF: 0.824 AC: 1198460 AN: 1454520 Hom.: 496201 Cov.: 33 AF XY: 0.823 AC XY: 595991 AN XY: 723882

African (AFR) AF: 0.936 AC: 31167 AN: 33300

American (AMR) AF: 0.752 AC: 33416 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.917 AC: 23917 AN: 26068

East Asian (EAS) AF: 0.564 AC: 22302 AN: 39554

South Asian (SAS) AF: 0.784 AC: 67453 AN: 85992

European-Finnish (FIN) AF: 0.801 AC: 42693 AN: 53290

Middle Eastern (MID) AF: 0.876 AC: 5045 AN: 5758

European-Non Finnish (NFE) AF: 0.834 AC: 922906 AN: 1105980

Other (OTH) AF: 0.824 AC: 49561 AN: 60126

GnomAD4 genome AF: 0.844 AC: 128393 AN: 152120 Hom.: 54671 Cov.: 32 AF XY: 0.839 AC XY: 62383 AN XY: 74346

African (AFR) AF: 0.929 AC: 38552 AN: 41492

American (AMR) AF: 0.794 AC: 12143 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.897 AC: 3111 AN: 3468

East Asian (EAS) AF: 0.556 AC: 2875 AN: 5172

South Asian (SAS) AF: 0.763 AC: 3677 AN: 4822

European-Finnish (FIN) AF: 0.804 AC: 8527 AN: 10604

Middle Eastern (MID) AF: 0.908 AC: 267 AN: 294

European-Non Finnish (NFE) AF: 0.834 AC: 56695 AN: 67950

Other (OTH) AF: 0.827 AC: 1745 AN: 2110

Alfa AF: 0.823 Hom.: 13868

Bravo AF: 0.847

Asia WGS AF: 0.656 AC: 2280 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.7
DANN	Benign	0.43
PhyloP100		-1.8
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: rs2734281; hg19: chr17-48273439; COSMIC: COSV56803371; COSMIC: COSV56803371;