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GeneBe

17-50190862-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000088.4(COL1A1):c.2298T>C(p.Thr766=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,614,154 control chromosomes in the GnomAD database, including 806,944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 1.0 ( 76076 hom., cov: 32)
Exomes 𝑓: 1.0 ( 730868 hom. )

Consequence

COL1A1
NM_000088.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.615
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.54).
BP6
Variant 17-50190862-A-G is Benign according to our data. Variant chr17-50190862-A-G is described in ClinVar as [Benign]. Clinvar id is 254947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50190862-A-G is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL1A1NM_000088.4 linkuse as main transcriptc.2298T>C p.Thr766= synonymous_variant 33/51 ENST00000225964.10
COL1A1XM_011524341.2 linkuse as main transcriptc.2100T>C p.Thr700= synonymous_variant 30/48
COL1A1XM_005257058.5 linkuse as main transcriptc.2298T>C p.Thr766= synonymous_variant 33/49
COL1A1XM_005257059.5 linkuse as main transcriptc.1380T>C p.Thr460= synonymous_variant 20/38

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL1A1ENST00000225964.10 linkuse as main transcriptc.2298T>C p.Thr766= synonymous_variant 33/511 NM_000088.4 P1
COL1A1ENST00000494334.1 linkuse as main transcriptn.63T>C non_coding_transcript_exon_variant 1/22
COL1A1ENST00000476387.1 linkuse as main transcript downstream_gene_variant 2

Frequencies

GnomAD3 genomes
AF:
1.00
AC:
152096
AN:
152158
Hom.:
76017
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.999
Gnomad AMI
AF:
1.00
Gnomad AMR
AF:
0.999
Gnomad ASJ
AF:
1.00
Gnomad EAS
AF:
1.00
Gnomad SAS
AF:
1.00
Gnomad FIN
AF:
1.00
Gnomad MID
AF:
1.00
Gnomad NFE
AF:
1.00
Gnomad OTH
AF:
1.00
GnomAD3 exomes
AF:
1.00
AC:
251280
AN:
251308
Hom.:
125626
AF XY:
1.00
AC XY:
135845
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.999
Gnomad AMR exome
AF:
1.00
Gnomad ASJ exome
AF:
1.00
Gnomad EAS exome
AF:
1.00
Gnomad SAS exome
AF:
1.00
Gnomad FIN exome
AF:
1.00
Gnomad NFE exome
AF:
1.00
Gnomad OTH exome
AF:
1.00
GnomAD4 exome
AF:
1.00
AC:
1461806
AN:
1461878
Hom.:
730868
Cov.:
61
AF XY:
1.00
AC XY:
727210
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.999
Gnomad4 AMR exome
AF:
1.00
Gnomad4 ASJ exome
AF:
1.00
Gnomad4 EAS exome
AF:
1.00
Gnomad4 SAS exome
AF:
1.00
Gnomad4 FIN exome
AF:
1.00
Gnomad4 NFE exome
AF:
1.00
Gnomad4 OTH exome
AF:
1.00
GnomAD4 genome
AF:
1.00
AC:
152214
AN:
152276
Hom.:
76076
Cov.:
32
AF XY:
1.00
AC XY:
74432
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.999
Gnomad4 AMR
AF:
0.999
Gnomad4 ASJ
AF:
1.00
Gnomad4 EAS
AF:
1.00
Gnomad4 SAS
AF:
1.00
Gnomad4 FIN
AF:
1.00
Gnomad4 NFE
AF:
1.00
Gnomad4 OTH
AF:
1.00
Alfa
AF:
1.00
Hom.:
21952
Bravo
AF:
0.999
Asia WGS
AF:
1.00
AC:
3478
AN:
3478
EpiCase
AF:
1.00
EpiControl
AF:
1.00

ClinVar

Significance: Benign
Submissions summary: Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2016This 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. -
Ehlers-Danlos syndrome, arthrochalasia type Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Osteogenesis imperfecta type I Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Osteogenesis imperfecta Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Osteogenesis imperfecta type III Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
Infantile cortical hyperostosis;C0023931:Osteogenesis imperfecta type I;C0029456:Osteoporosis;C0268358:Osteogenesis imperfecta, perinatal lethal;C0268362:Osteogenesis imperfecta type III;C0268363:Osteogenesis imperfecta with normal sclerae, dominant form;C4551623:Ehlers-Danlos syndrome, arthrochalasia type;C5436842:Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 Benign:1
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 09, 2021- -
Osteogenesis imperfecta with normal sclerae, dominant form Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
Osteogenesis imperfecta, perinatal lethal Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
Infantile cortical hyperostosis Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 04, 2018This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.54
Cadd
Benign
10
Dann
Benign
0.62

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2734272; hg19: chr17-48268223; COSMIC: COSV56808096; COSMIC: COSV56808096; API