chr17-50184337-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000088.4(COL1A1):​c.*1165C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00772 in 231,932 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0077 ( 12 hom., cov: 31)
Exomes 𝑓: 0.0078 ( 4 hom. )

Consequence

COL1A1
NM_000088.4 3_prime_UTR

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.498
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 -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 17-50184337-G-C is Benign according to our data. Variant chr17-50184337-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 324059.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=3}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00767 (1168/152186) while in subpopulation NFE AF= 0.00992 (675/68020). AF 95% confidence interval is 0.0093. There are 12 homozygotes in gnomad4. There are 645 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1168 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL1A1NM_000088.4 linkuse as main transcriptc.*1165C>G 3_prime_UTR_variant 51/51 ENST00000225964.10
COL1A1XM_005257058.5 linkuse as main transcriptc.*1165C>G 3_prime_UTR_variant 49/49
COL1A1XM_005257059.5 linkuse as main transcriptc.*1165C>G 3_prime_UTR_variant 38/38
COL1A1XM_011524341.2 linkuse as main transcriptc.*1165C>G 3_prime_UTR_variant 48/48

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL1A1ENST00000225964.10 linkuse as main transcriptc.*1165C>G 3_prime_UTR_variant 51/511 NM_000088.4 P1

Frequencies

GnomAD3 genomes
AF:
0.00768
AC:
1168
AN:
152068
Hom.:
12
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00133
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00183
Gnomad ASJ
AF:
0.0205
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00207
Gnomad FIN
AF:
0.0300
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00992
Gnomad OTH
AF:
0.00430
GnomAD4 exome
AF:
0.00781
AC:
623
AN:
79746
Hom.:
4
Cov.:
0
AF XY:
0.00789
AC XY:
291
AN XY:
36882
show subpopulations
Gnomad4 AFR exome
AF:
0.00133
Gnomad4 AMR exome
AF:
0.00164
Gnomad4 ASJ exome
AF:
0.0204
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00575
Gnomad4 FIN exome
AF:
0.0238
Gnomad4 NFE exome
AF:
0.00929
Gnomad4 OTH exome
AF:
0.00587
GnomAD4 genome
AF:
0.00767
AC:
1168
AN:
152186
Hom.:
12
Cov.:
31
AF XY:
0.00867
AC XY:
645
AN XY:
74402
show subpopulations
Gnomad4 AFR
AF:
0.00133
Gnomad4 AMR
AF:
0.00183
Gnomad4 ASJ
AF:
0.0205
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00207
Gnomad4 FIN
AF:
0.0300
Gnomad4 NFE
AF:
0.00992
Gnomad4 OTH
AF:
0.00426
Alfa
AF:
0.0114
Hom.:
1
Bravo
AF:
0.00530

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingGeneDxSep 11, 2021- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2023COL1A1: BS1, BS2 -
Infantile cortical hyperostosis Uncertain:1
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
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. -
Ehlers-Danlos syndrome, arthrochalasia type 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
CADD
Benign
8.2
DANN
Benign
0.61

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: rs149419718; hg19: chr17-48261698; API