17-50189433-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 3P and 7B. PM1PP2BP4_ModerateBP6BS2

The NM_000088.4(COL1A1):c.2773C>G(p.Pro925Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,612,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P925S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

COL1A1
NM_000088.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 3.24

Publications

1 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: Likely_benign. The variant received -4 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_000088.4

PP2

Missense variant in the COL1A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 368 curated pathogenic missense variants (we use a threshold of 10). The gene has 98 curated benign missense variants. Gene score misZ: 3.5319 (above the threshold of 3.09). Trascript score misZ: 5.7733 (above the threshold of 3.09). GenCC associations: The gene is linked to high bone mass osteogenesis imperfecta, Ehlers-Danlos syndrome, arthrochalasia type, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, Caffey disease, osteogenesis imperfecta type 4, osteogenesis imperfecta type 3, Ehlers-Danlos syndrome, classic type, Ehlers-Danlos syndrome, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1, Ehlers-Danlos syndrome, classic type, 1, Ehlers-Danlos/osteogenesis imperfecta syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.26068354).

BP6

Variant 17-50189433-G-C is Benign according to our data. Variant chr17-50189433-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1001743.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL1A1	NM_000088.4 link	c.2773C>G	p.Pro925Ala	missense_variant	Exon 39 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2 link	c.2575C>G	p.Pro859Ala	missense_variant	Exon 36 of 48		XP_011522643.1
COL1A1	XM_005257059.5 link	c.1855C>G	p.Pro619Ala	missense_variant	Exon 26 of 38		XP_005257116.2
COL1A1	XM_005257058.5 link	c.2667+246C>G		intron_variant	Intron 38 of 48		XP_005257115.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10 link	c.2773C>G	p.Pro925Ala	missense_variant	Exon 39 of 51	1	NM_000088.4	ENSP00000225964.6

Frequencies

GnomAD3 genomes

AF:

0.0000463

AC:

AN:

151098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000886

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000400

AC:

AN:

250238

AF XY:

0.0000369

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000499

AC:

AN:

1461730

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000630

AC:

AN:

1111982

Other (OTH)

AF:

0.0000497

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000463

AC:

AN:

151098

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73840

show subpopulations

African (AFR)

AF:

0.0000244

AC:

AN:

41058

American (AMR)

AF:

0.00

AC:

AN:

15202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5078

South Asian (SAS)

AF:

0.00

AC:

AN:

4774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000886

AC:

AN:

67694

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000450

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Mar 20, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The COL1A1 c.2773C>G; p.Pro925Ala variant (rs772929903), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 1001743). This variant is observed in the general population with an overall allele frequency of 0.004% (11/281404 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.271). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Jun 25, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease (HGMD); In silico analysis suggests that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Ehlers-Danlos syndrome, classic type, 1

Uncertain:1

Sep 21, 2018

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Osteogenesis imperfecta type I

Benign:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.037

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.88

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.090

FATHMM_MKL

Benign

0.59

M_CAP

Benign

0.068

MetaRNN

Benign

0.26

MetaSVM

Uncertain

-0.25

PhyloP100

3.2

PrimateAI

Benign

0.44

PROVEAN

Benign

0.32

REVEL

Benign

0.27

Sift

Benign

1.0

Sift4G

Benign

0.96

Vest4

0.29

MVP

0.73

MPC

0.54

ClinPred

0.099

GERP RS

4.6

gMVP

0.30

Mutation Taster

=89/11

polymorphism

(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