rs148275339

Positions:

• chr17-50193012-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000088.4(COL1A1):​c.1803C>T​(p.Pro601=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00782 in 1,614,064 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (66 hom.)
• Consequence: COL1A1 NM_000088.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.53

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 17-50193012-G-A is Benign according to our data. Variant chr17-50193012-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 289176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50193012-G-A is described in Lovd as [Benign]. Variant chr17-50193012-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00804 (1225/152302) while in subpopulation AMR AF= 0.0116 (178/15300). AF 95% confidence interval is 0.0102. There are 8 homozygotes in gnomad4. There are 590 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1225 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.1803C>T	p.Pro601=	synonymous_variant	26/51	ENST00000225964.10
COL1A1	XM_011524341.2	c.1605C>T	p.Pro535=	synonymous_variant	23/48
COL1A1	XM_005257058.5	c.1803C>T	p.Pro601=	synonymous_variant	26/49
COL1A1	XM_005257059.5	c.958-319C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.1803C>T	p.Pro601=	synonymous_variant	26/51	1	NM_000088.4	P1
COL1A1	ENST00000476387.1	n.152C>T		non_coding_transcript_exon_variant	2/9	2

Frequencies

GnomAD3 genomes AF: 0.00802 AC: 1220 AN: 152184 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00733

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00941

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00755 AC: 1891 AN: 250510 Hom.: 16 AF XY: 0.00791 AC XY: 1071 AN XY: 135426

Gnomad AFR exome AF: 0.00681

Gnomad AMR exome AF: 0.00715

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00612

Gnomad FIN exome AF: 0.00417

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.00967

GnomAD4 exome AF: 0.00779 AC: 11392 AN: 1461762 Hom.: 66 Cov.: 34 AF XY: 0.00782 AC XY: 5688 AN XY: 727170

Gnomad4 AFR exome AF: 0.00675

Gnomad4 AMR exome AF: 0.00733

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00559

Gnomad4 FIN exome AF: 0.00513

Gnomad4 NFE exome AF: 0.00855

Gnomad4 OTH exome AF: 0.00785

GnomAD4 genome AF: 0.00804 AC: 1225 AN: 152302 Hom.: 8 Cov.: 32 AF XY: 0.00792 AC XY: 590 AN XY: 74472

Gnomad4 AFR AF: 0.00731

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00282

Gnomad4 NFE AF: 0.00941

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00830 Hom.: 2

Bravo AF: 0.00849

Asia WGS AF: 0.0140 AC: 49 AN: 3478

EpiCase AF: 0.0105

EpiControl AF: 0.0126

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	COL1A1: BP4, BP7, BS1, BS2 -

Osteogenesis imperfecta Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jan 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 27, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2016	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. -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 10, 2022

- -

Ehlers-Danlos syndrome, arthrochalasia type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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. -

Infantile cortical hyperostosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2019

This 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. -

Osteogenesis imperfecta type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	2.2
DANN	Benign	0.92

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

LitVar

Other links and lift over

dbSNP: rs148275339; hg19: chr17-48270373;