rs35231764

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.588+33T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,612,788 control chromosomes in the GnomAD database, including 69,541 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 5025 hom., cov: 31)

Exomes 𝑓: 0.29 ( 64516 hom. )

Consequence

COL1A1
NM_000088.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0580

Publications

12 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=-0.8).

BP6

Variant 17-50198128-A-G is Benign according to our data. Variant chr17-50198128-A-G is described in ClinVar as Benign. ClinVar VariationId is 675050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4 link	c.588+33T>C	intron_variant	Intron 7 of 50	ENST00000225964.10	NP_000079.2	P02452
COL1A1	XM_011524341.2 link	c.588+33T>C	intron_variant	Intron 7 of 47		XP_011522643.1
COL1A1	XM_005257058.5 link	c.588+33T>C	intron_variant	Intron 7 of 48		XP_005257115.2
COL1A1	XM_005257059.5 link	c.588+33T>C	intron_variant	Intron 7 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10 link	c.588+33T>C		intron_variant	Intron 7 of 50	1	NM_000088.4	ENSP00000225964.6		P02452
COL1A1	ENST00000495677.1 link	n.315+33T>C		intron_variant	Intron 2 of 7	3

Frequencies

GnomAD3 genomes

AF:

0.232

AC:

35168

AN:

151910

Hom.:

5022

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0587

Gnomad AMI

AF:

0.389

Gnomad AMR

AF:

0.266

Gnomad ASJ

AF:

0.393

Gnomad EAS

AF:

0.212

Gnomad SAS

AF:

0.285

Gnomad FIN

AF:

0.314

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.302

Gnomad OTH

AF:

0.255

GnomAD2 exomes

AF:

0.278

AC:

69703

AN:

250554

AF XY:

0.284

show subpopulations

Gnomad AFR exome

AF:

0.0538

Gnomad AMR exome

AF:

0.264

Gnomad ASJ exome

AF:

0.390

Gnomad EAS exome

AF:

0.207

Gnomad FIN exome

AF:

0.300

Gnomad NFE exome

AF:

0.309

Gnomad OTH exome

AF:

0.294

GnomAD4 exome

AF:

0.292

AC:

427009

AN:

1460760

Hom.:

64516

Cov.:

AF XY:

0.293

AC XY:

213023

AN XY:

726736

show subpopulations

African (AFR)

AF:

0.0519

AC:

1738

AN:

33460

American (AMR)

AF:

0.261

AC:

11687

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.391

AC:

10225

AN:

26128

East Asian (EAS)

AF:

0.170

AC:

6739

AN:

39696

South Asian (SAS)

AF:

0.285

AC:

24561

AN:

86238

European-Finnish (FIN)

AF:

0.298

AC:

15923

AN:

53398

Middle Eastern (MID)

AF:

0.334

AC:

1923

AN:

5764

European-Non Finnish (NFE)

AF:

0.303

AC:

336891

AN:

1110990

Other (OTH)

AF:

0.287

AC:

17322

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

16101

32203

48304

64406

80507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10978

21956

32934

43912

54890

<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:

0.231

AC:

35166

AN:

152028

Hom.:

5025

Cov.:

AF XY:

0.233

AC XY:

17295

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0586

AC:

2433

AN:

41506

American (AMR)

AF:

0.266

AC:

4061

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.393

AC:

1361

AN:

3460

East Asian (EAS)

AF:

0.211

AC:

1090

AN:

5154

South Asian (SAS)

AF:

0.286

AC:

1374

AN:

4808

European-Finnish (FIN)

AF:

0.314

AC:

3324

AN:

10572

Middle Eastern (MID)

AF:

0.364

AC:

107

AN:

294

European-Non Finnish (NFE)

AF:

0.302

AC:

20523

AN:

67938

Other (OTH)

AF:

0.255

AC:

539

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1282

2564

3845

5127

6409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

364

728

1092

1456

1820

<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:

0.273

Hom.:

3010

Bravo

AF:

0.219

Asia WGS

AF:

0.230

AC:

799

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 18, 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

-0.80

CADD

Benign

9.1

(source)

DANN

Benign

0.78

PhyloP100

-0.058

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