chr17-50196542-A-C

Variant names:

• chr17-50196542-A-C
• rs17639446
• NM_000088.4:c.859-14T>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.859-14T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,614,024 control chromosomes in the GnomAD database, including 9,749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (595 hom., cov: 32)
  • Exomes 𝑓: 0.10 (9154 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.645
• Publications: 18 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=-0.77).
• BP6: Variant 17-50196542-A-C is Benign according to our data. Variant chr17-50196542-A-C is described in ClinVar as Benign. ClinVar VariationId is 254951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.112 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.859-14T>G		intron	N/A	NP_000079.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	ENST00000225964.10	TSL:1 MANE Select	c.859-14T>G		intron	N/A	ENSP00000225964.6
	COL1A1	ENST00000861334.1		c.859-14T>G		intron	N/A	ENSP00000531393.1
	COL1A1	ENST00000861339.1		c.859-14T>G		intron	N/A	ENSP00000531398.1

Frequencies

GnomAD3 genomes AF: 0.0764 AC: 11630 AN: 152134 Hom.: 595 Cov.: 32

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.0927

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0270

Gnomad FIN AF: 0.0419

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.0956

GnomAD2 exomes AF: 0.0782 AC: 19663 AN: 251474 AF XY: 0.0795

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.0615

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0453

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.0961

GnomAD4 exome AF: 0.105 AC: 153074 AN: 1461772 Hom.: 9154 Cov.: 39 AF XY: 0.103 AC XY: 74727 AN XY: 727204

African (AFR) AF: 0.0203 AC: 679 AN: 33478

American (AMR) AF: 0.0648 AC: 2899 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3614 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0320 AC: 2764 AN: 86258

European-Finnish (FIN) AF: 0.0482 AC: 2574 AN: 53416

Middle Eastern (MID) AF: 0.148 AC: 856 AN: 5768

European-Non Finnish (NFE) AF: 0.120 AC: 133514 AN: 1111898

Other (OTH) AF: 0.102 AC: 6171 AN: 60394

GnomAD4 genome AF: 0.0764 AC: 11627 AN: 152252 Hom.: 595 Cov.: 32 AF XY: 0.0721 AC XY: 5367 AN XY: 74450

African (AFR) AF: 0.0224 AC: 932 AN: 41548

American (AMR) AF: 0.0926 AC: 1416 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 473 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0270 AC: 130 AN: 4814

European-Finnish (FIN) AF: 0.0419 AC: 445 AN: 10614

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.114 AC: 7787 AN: 68014

Other (OTH) AF: 0.0951 AC: 201 AN: 2114

Alfa AF: 0.0935 Hom.: 196

Bravo AF: 0.0794

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Ehlers-Danlos syndrome, arthrochalasia type (1)
-	-	1	Infantile cortical hyperostosis (1)
-	-	1	not provided (1)
-	-	1	Osteogenesis imperfecta (1)
-	-	1	Osteogenesis imperfecta type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	15
DANN	Benign	0.81
PhyloP100		0.65
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: rs17639446; hg19: chr17-48273903; COSMIC: COSV56806929;