17-50196078-T-C

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.1002+77A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.826 in 1,606,640 control chromosomes in the GnomAD database, including 550,872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.84 ( 54671 hom., cov: 32)

Exomes 𝑓: 0.82 ( 496201 hom. )

Consequence

COL1A1
NM_000088.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.79

Publications

10 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 17-50196078-T-C is Benign according to our data. Variant chr17-50196078-T-C is described in ClinVar as Benign. ClinVar VariationId is 674978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4 link	c.1002+77A>G	intron_variant	Intron 15 of 50	ENST00000225964.10	NP_000079.2	P02452
COL1A1	XM_011524341.2 link	c.957+236A>G	intron_variant	Intron 14 of 47		XP_011522643.1
COL1A1	XM_005257058.5 link	c.1002+77A>G	intron_variant	Intron 15 of 48		XP_005257115.2
COL1A1	XM_005257059.5 link	c.957+236A>G	intron_variant	Intron 14 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10 link	c.1002+77A>G		intron_variant	Intron 15 of 50	1	NM_000088.4	ENSP00000225964.6		P02452
COL1A1	ENST00000485870.1 link	n.*1A>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.844

AC:

128296

AN:

152002

Hom.:

54633

Cov.:

show subpopulations

Gnomad AFR

AF:

0.929

Gnomad AMI

AF:

0.878

Gnomad AMR

AF:

0.794

Gnomad ASJ

AF:

0.897

Gnomad EAS

AF:

0.556

Gnomad SAS

AF:

0.763

Gnomad FIN

AF:

0.804

Gnomad MID

AF:

0.918

Gnomad NFE

AF:

0.834

Gnomad OTH

AF:

0.833

GnomAD4 exome

AF:

0.824

AC:

1198460

AN:

1454520

Hom.:

496201

Cov.:

AF XY:

0.823

AC XY:

595991

AN XY:

723882

show subpopulations

African (AFR)

AF:

0.936

AC:

31167

AN:

33300

American (AMR)

AF:

0.752

AC:

33416

AN:

44452

Ashkenazi Jewish (ASJ)

AF:

0.917

AC:

23917

AN:

26068

East Asian (EAS)

AF:

0.564

AC:

22302

AN:

39554

South Asian (SAS)

AF:

0.784

AC:

67453

AN:

85992

European-Finnish (FIN)

AF:

0.801

AC:

42693

AN:

53290

Middle Eastern (MID)

AF:

0.876

AC:

5045

AN:

5758

European-Non Finnish (NFE)

AF:

0.834

AC:

922906

AN:

1105980

Other (OTH)

AF:

0.824

AC:

49561

AN:

60126

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

12036

24072

36108

48144

60180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20872

41744

62616

83488

104360

<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:

0.844

AC:

128393

AN:

152120

Hom.:

54671

Cov.:

AF XY:

0.839

AC XY:

62383

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.929

AC:

38552

AN:

41492

American (AMR)

AF:

0.794

AC:

12143

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.897

AC:

3111

AN:

3468

East Asian (EAS)

AF:

0.556

AC:

2875

AN:

5172

South Asian (SAS)

AF:

0.763

AC:

3677

AN:

4822

European-Finnish (FIN)

AF:

0.804

AC:

8527

AN:

10604

Middle Eastern (MID)

AF:

0.908

AC:

267

AN:

294

European-Non Finnish (NFE)

AF:

0.834

AC:

56695

AN:

67950

Other (OTH)

AF:

0.827

AC:

1745

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1010

2021

3031

4042

5052

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

884

1768

2652

3536

4420

<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:

0.823

Hom.:

13868

Bravo

AF:

0.847

Asia WGS

AF:

0.656

AC:

2280

AN:

3478

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 14, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.7

(source)

DANN

Benign

0.43

PhyloP100

-1.8

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