chr17-50186542-A-G

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.3815-35T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,613,676 control chromosomes in the GnomAD database, including 23,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3244 hom., cov: 32)

Exomes 𝑓: 0.16 ( 20724 hom. )

Consequence

COL1A1
NM_000088.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.00700

Publications

20 publications found

Variant links:

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=-0.86).

BP6

Variant 17-50186542-A-G is Benign according to our data. Variant chr17-50186542-A-G is described in ClinVar as Benign. ClinVar VariationId is 674809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4 link	c.3815-35T>C	intron_variant	Intron 48 of 50	ENST00000225964.10	NP_000079.2	P02452
COL1A1	XM_011524341.2 link	c.3617-35T>C	intron_variant	Intron 45 of 47		XP_011522643.1
COL1A1	XM_005257058.5 link	c.3545-35T>C	intron_variant	Intron 46 of 48		XP_005257115.2
COL1A1	XM_005257059.5 link	c.2897-35T>C	intron_variant	Intron 35 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10 link	c.3815-35T>C		intron_variant	Intron 48 of 50	1	NM_000088.4	ENSP00000225964.6		P02452
COL1A1	ENST00000510710.3 link	n.484-35T>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.191

AC:

28992

AN:

151902

Hom.:

3241

Cov.:

show subpopulations

Gnomad AFR

AF:

0.290

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.125

Gnomad EAS

AF:

0.358

Gnomad SAS

AF:

0.254

Gnomad FIN

AF:

0.153

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.145

Gnomad OTH

AF:

0.181

GnomAD2 exomes

AF:

0.179

AC:

44868

AN:

251100

AF XY:

0.182

show subpopulations

Gnomad AFR exome

AF:

0.298

Gnomad AMR exome

AF:

0.0701

Gnomad ASJ exome

AF:

0.137

Gnomad EAS exome

AF:

0.364

Gnomad FIN exome

AF:

0.160

Gnomad NFE exome

AF:

0.148

Gnomad OTH exome

AF:

0.150

GnomAD4 exome

AF:

0.159

AC:

232358

AN:

1461656

Hom.:

20724

Cov.:

AF XY:

0.162

AC XY:

118140

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.297

AC:

9953

AN:

33478

American (AMR)

AF:

0.0735

AC:

3286

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

3538

AN:

26136

East Asian (EAS)

AF:

0.338

AC:

13401

AN:

39700

South Asian (SAS)

AF:

0.269

AC:

23227

AN:

86248

European-Finnish (FIN)

AF:

0.158

AC:

8449

AN:

53374

Middle Eastern (MID)

AF:

0.170

AC:

980

AN:

5768

European-Non Finnish (NFE)

AF:

0.143

AC:

159209

AN:

1111844

Other (OTH)

AF:

0.171

AC:

10315

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

12351

24702

37053

49404

61755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5882

11764

17646

23528

29410

<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:

0.191

AC:

29029

AN:

152020

Hom.:

3244

Cov.:

AF XY:

0.193

AC XY:

14313

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.290

AC:

12035

AN:

41438

American (AMR)

AF:

0.103

AC:

1571

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

432

AN:

3466

East Asian (EAS)

AF:

0.358

AC:

1841

AN:

5144

South Asian (SAS)

AF:

0.254

AC:

1224

AN:

4812

European-Finnish (FIN)

AF:

0.153

AC:

1623

AN:

10578

Middle Eastern (MID)

AF:

0.173

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.145

AC:

9832

AN:

67972

Other (OTH)

AF:

0.182

AC:

385

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1152

2304

3457

4609

5761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

322

644

966

1288

1610

<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:

0.162

Hom.:

3354

Bravo

AF:

0.191

Asia WGS

AF:

0.309

AC:

1073

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 19, 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. -

Osteogenesis imperfecta type III

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteogenesis imperfecta with normal sclerae, dominant form

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome, arthrochalasia type

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteogenesis imperfecta, perinatal lethal

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteogenesis imperfecta type I

Benign:1

Jul 22, 2021

Genome-Nilou Lab

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

-0.86

CADD

Benign

1.3

(source)

DANN

Benign

0.57

PhyloP100

-0.0070

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