rs16948767

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.642+18A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,613,074 control chromosomes in the GnomAD database, including 5,595 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 2628 hom., cov: 31)

Exomes 𝑓: 0.031 ( 2967 hom. )

Consequence

COL1A1
NM_000088.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.760

Publications

6 publications found

Variant links:

COSMIC-nc: COSV56806394

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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
COL1A1-related Ehlers-Danlos syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, Ambry Genetics
Ehlers-Danlos syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Ehlers-Danlos syndrome, arthrochalasia type
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
osteogenesis imperfecta
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
osteogenesis imperfecta type 1
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
osteogenesis imperfecta type 2
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
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: ClinGen, G2P, Orphanet
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=-0.81).

BP6

Variant 17-50197931-T-G is Benign according to our data. Variant chr17-50197931-T-G is described in ClinVar as Benign. ClinVar VariationId is 254950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000088.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	NM_000088.4	MANE Select	c.642+18A>C		intron	N/A	NP_000079.2	P02452

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COL1A1	ENST00000225964.10	TSL:1 MANE Select	c.642+18A>C	intron	N/A	ENSP00000225964.6	P02452
COL1A1	ENST00000861334.1		c.642+18A>C	intron	N/A	ENSP00000531393.1
COL1A1	ENST00000861339.1		c.642+18A>C	intron	N/A	ENSP00000531398.1

Frequencies

GnomAD3 genomes

AF:

0.115

AC:

17408

AN:

151992

Hom.:

2617

Cov.:

show subpopulations

Gnomad AFR

AF:

0.351

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0474

Gnomad ASJ

AF:

0.0276

Gnomad EAS

AF:

0.00943

Gnomad SAS

AF:

0.0572

Gnomad FIN

AF:

0.0130

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0213

Gnomad OTH

AF:

0.0831

GnomAD2 exomes

AF:

0.0476

AC:

11935

AN:

250590

AF XY:

0.0435

show subpopulations

Gnomad AFR exome

AF:

0.358

Gnomad AMR exome

AF:

0.0276

Gnomad ASJ exome

AF:

0.0223

Gnomad EAS exome

AF:

0.00625

Gnomad FIN exome

AF:

0.0141

Gnomad NFE exome

AF:

0.0235

Gnomad OTH exome

AF:

0.0343

GnomAD4 exome

AF:

0.0312

AC:

45538

AN:

1460964

Hom.:

2967

Cov.:

AF XY:

0.0313

AC XY:

22757

AN XY:

726896

show subpopulations

African (AFR)

AF:

0.364

AC:

12169

AN:

33426

American (AMR)

AF:

0.0297

AC:

1328

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0217

AC:

568

AN:

26132

East Asian (EAS)

AF:

0.00642

AC:

255

AN:

39694

South Asian (SAS)

AF:

0.0594

AC:

5126

AN:

86234

European-Finnish (FIN)

AF:

0.0148

AC:

789

AN:

53410

Middle Eastern (MID)

AF:

0.0550

AC:

317

AN:

5764

European-Non Finnish (NFE)

AF:

0.0200

AC:

22211

AN:

1111236

Other (OTH)

AF:

0.0460

AC:

2775

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

2015

4029

6044

8058

10073

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

984

1968

2952

3936

4920

<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:

0.115

AC:

17446

AN:

152110

Hom.:

2628

Cov.:

AF XY:

0.112

AC XY:

8317

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.351

AC:

14525

AN:

41410

American (AMR)

AF:

0.0472

AC:

722

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0276

AC:

AN:

3472

East Asian (EAS)

AF:

0.00926

AC:

AN:

5182

South Asian (SAS)

AF:

0.0568

AC:

274

AN:

4822

European-Finnish (FIN)

AF:

0.0130

AC:

138

AN:

10602

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0213

AC:

1446

AN:

68004

Other (OTH)

AF:

0.0822

AC:

174

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

618

1237

1855

2474

3092

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

158

316

474

632

790

<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:

0.0465

Hom.:

1003

Bravo

AF:

0.127

Asia WGS

AF:

0.0510

AC:

176

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

not provided (1)

Osteogenesis imperfecta type I (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.0

(source)

DANN

Benign

0.57

PhyloP100

-0.76

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over