rs2075558

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.2451+103T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 1,243,044 control chromosomes in the GnomAD database, including 96,932 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10477 hom., cov: 31)

Exomes 𝑓: 0.38 ( 86455 hom. )

Consequence

COL1A1
NM_000088.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.11

Publications

11 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=-0.82).

BP6

Variant 17-50190224-A-C is Benign according to our data. Variant chr17-50190224-A-C is described in ClinVar as Benign. ClinVar VariationId is 1268888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4 link	c.2451+103T>G	intron_variant	Intron 35 of 50	ENST00000225964.10	NP_000079.2	P02452
COL1A1	XM_011524341.2 link	c.2253+103T>G	intron_variant	Intron 32 of 47		XP_011522643.1
COL1A1	XM_005257058.5 link	c.2451+103T>G	intron_variant	Intron 35 of 48		XP_005257115.2
COL1A1	XM_005257059.5 link	c.1533+103T>G	intron_variant	Intron 22 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10 link	c.2451+103T>G		intron_variant	Intron 35 of 50	1	NM_000088.4	ENSP00000225964.6		P02452
COL1A1	ENST00000494334.1 link	n.*85T>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.354

AC:

53719

AN:

151536

Hom.:

10463

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.169

Gnomad AMR

AF:

0.463

Gnomad ASJ

AF:

0.322

Gnomad EAS

AF:

0.787

Gnomad SAS

AF:

0.487

Gnomad FIN

AF:

0.413

Gnomad MID

AF:

0.232

Gnomad NFE

AF:

0.358

Gnomad OTH

AF:

0.362

GnomAD4 exome

AF:

0.381

AC:

416358

AN:

1091392

Hom.:

86455

Cov.:

AF XY:

0.385

AC XY:

214498

AN XY:

557764

show subpopulations

African (AFR)

AF:

0.219

AC:

5828

AN:

26594

American (AMR)

AF:

0.555

AC:

24320

AN:

43804

Ashkenazi Jewish (ASJ)

AF:

0.303

AC:

7063

AN:

23334

East Asian (EAS)

AF:

0.803

AC:

30464

AN:

37952

South Asian (SAS)

AF:

0.477

AC:

37422

AN:

78470

European-Finnish (FIN)

AF:

0.407

AC:

21400

AN:

52566

Middle Eastern (MID)

AF:

0.290

AC:

1463

AN:

5042

European-Non Finnish (NFE)

AF:

0.349

AC:

270559

AN:

775392

Other (OTH)

AF:

0.370

AC:

17839

AN:

48238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

14210

28420

42631

56841

71051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7360

14720

22080

29440

36800

<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:

0.355

AC:

53774

AN:

151652

Hom.:

10477

Cov.:

AF XY:

0.366

AC XY:

27110

AN XY:

74118

show subpopulations

African (AFR)

AF:

0.232

AC:

9595

AN:

41282

American (AMR)

AF:

0.464

AC:

7082

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.322

AC:

1116

AN:

3470

East Asian (EAS)

AF:

0.785

AC:

4012

AN:

5108

South Asian (SAS)

AF:

0.488

AC:

2349

AN:

4814

European-Finnish (FIN)

AF:

0.413

AC:

4362

AN:

10558

Middle Eastern (MID)

AF:

0.236

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.358

AC:

24264

AN:

67842

Other (OTH)

AF:

0.366

AC:

771

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1692

3384

5075

6767

8459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

534

1068

1602

2136

2670

<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:

0.357

Hom.:

1267

Bravo

AF:

0.354

Asia WGS

AF:

0.613

AC:

2128

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

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 25, 2018

GeneDx

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

-0.82

CADD

Benign

5.8

(source)

DANN

Benign

0.63

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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