rs2696247

Variant names:

• chr17-50192542-A-G
• rs2696247
• NM_000088.4:c.1930-14T>C

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.1930-14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,613,782 control chromosomes in the GnomAD database, including 19,716 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1707 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18009 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0100
• Publications: 25 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, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), 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), Orphanet, Genomics England PanelApp
• 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=-0.8).
• BP6: Variant 17-50192542-A-G is Benign according to our data. Variant chr17-50192542-A-G is described in ClinVar as Benign. ClinVar VariationId is 254946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.334 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.1930-14T>C		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.1930-14T>C		intron	N/A	ENSP00000225964.6	P02452
	COL1A1	ENST00000861334.1		c.1930-14T>C		intron	N/A	ENSP00000531393.1
	COL1A1	ENST00000861339.1		c.1930-14T>C		intron	N/A	ENSP00000531398.1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21422 AN: 152034 Hom.: 1703 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.152

GnomAD2 exomes AF: 0.171 AC: 42946 AN: 251156 AF XY: 0.176

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.346

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.149 AC: 217585 AN: 1461630 Hom.: 18009 Cov.: 36 AF XY: 0.153 AC XY: 111269 AN XY: 727124

African (AFR) AF: 0.105 AC: 3523 AN: 33478

American (AMR) AF: 0.153 AC: 6848 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3784 AN: 26134

East Asian (EAS) AF: 0.326 AC: 12928 AN: 39696

South Asian (SAS) AF: 0.269 AC: 23230 AN: 86250

European-Finnish (FIN) AF: 0.142 AC: 7562 AN: 53412

Middle Eastern (MID) AF: 0.150 AC: 867 AN: 5768

European-Non Finnish (NFE) AF: 0.135 AC: 149580 AN: 1111788

Other (OTH) AF: 0.153 AC: 9263 AN: 60386

GnomAD4 genome AF: 0.141 AC: 21436 AN: 152152 Hom.: 1707 Cov.: 32 AF XY: 0.145 AC XY: 10753 AN XY: 74382

African (AFR) AF: 0.109 AC: 4523 AN: 41514

American (AMR) AF: 0.144 AC: 2201 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 504 AN: 3468

East Asian (EAS) AF: 0.347 AC: 1791 AN: 5156

South Asian (SAS) AF: 0.260 AC: 1253 AN: 4824

European-Finnish (FIN) AF: 0.135 AC: 1425 AN: 10590

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9337 AN: 67990

Other (OTH) AF: 0.154 AC: 326 AN: 2114

Alfa AF: 0.144 Hom.: 1117

Bravo AF: 0.138

Asia WGS AF: 0.303 AC: 1051 AN: 3478

ClinVar

ClinVar submissions

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	-0.80
CADD	Benign	8.9
DANN	Benign	0.84
PhyloP100		-0.010
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2696247;

hg19: chr17-48269903;

COSMIC: COSV56802824;

COSMIC: COSV56802824;