rs17639446

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.645

Publications

18 publications found

Variant links:

COSMIC-nc: COSV56806929

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

COL1A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4 link	c.859-14T>G	intron_variant	Intron 12 of 50	ENST00000225964.10	NP_000079.2	P02452
COL1A1	XM_011524341.2 link	c.859-14T>G	intron_variant	Intron 12 of 47		XP_011522643.1
COL1A1	XM_005257058.5 link	c.859-14T>G	intron_variant	Intron 12 of 48		XP_005257115.2
COL1A1	XM_005257059.5 link	c.859-14T>G	intron_variant	Intron 12 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL1A1	ENST00000225964.10 link	c.859-14T>G	intron_variant	Intron 12 of 50	1	NM_000088.4	ENSP00000225964.6	P02452
COL1A1	ENST00000485870.1 link	n.54T>G	non_coding_transcript_exon_variant	Exon 1 of 2	3
COL1A1	ENST00000495677.1 link	n.586-14T>G	intron_variant	Intron 7 of 7	3

Frequencies

GnomAD3 genomes

AF:

0.0764

AC:

11630

AN:

152134

Hom.:

595

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.103

AC XY:

74727

AN XY:

727204

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

8349

16698

25047

33396

41745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4798

9596

14394

19192

23990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0764

AC:

11627

AN:

152252

Hom.:

595

Cov.:

AF XY:

0.0721

AC XY:

5367

AN XY:

74450

show subpopulations

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:

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:

AN:

292

European-Non Finnish (NFE)

AF:

0.114

AC:

7787

AN:

68014

Other (OTH)

AF:

0.0951

AC:

201

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

562

1124

1687

2249

2811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

264

396

528

660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0935

Hom.:

196

Bravo

AF:

0.0794

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 03, 2016

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 26, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteogenesis imperfecta

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Ehlers-Danlos syndrome, arthrochalasia type

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Infantile cortical hyperostosis

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Osteogenesis imperfecta type I

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

0.65

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over