rs17639446

chr17-50196542-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000088.4(COL1A1):c.859-14T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,614,024 control chromosomes in the GnomAD database, including 9,749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (595 hom., cov: 32)
  • Exomes 𝑓: 0.10 (9154 hom.)
• Consequence: COL1A1 NM_000088.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.645

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 17-50196542-A-C is Benign according to our data. Variant chr17-50196542-A-C is described in ClinVar as [Benign]. Clinvar id is 254951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50196542-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.859-14T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000225964.10
COL1A1	XM_005257058.5	c.859-14T>G		splice_polypyrimidine_tract_variant, intron_variant
COL1A1	XM_005257059.5	c.859-14T>G		splice_polypyrimidine_tract_variant, intron_variant
COL1A1	XM_011524341.2	c.859-14T>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.859-14T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000088.4	P1
COL1A1	ENST00000485870.1	n.54T>G		non_coding_transcript_exon_variant	1/2	3
COL1A1	ENST00000495677.1	n.586-14T>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0764 AC: 11630 AN: 152134 Hom.: 595 Cov.: 32

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.0927

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0270

Gnomad FIN AF: 0.0419

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.0956

GnomAD3 exomes AF: 0.0782 AC: 19663 AN: 251474 Hom.: 1059 AF XY: 0.0795 AC XY: 10811 AN XY: 135910

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.0615

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0303

Gnomad FIN exome AF: 0.0453

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.0961

GnomAD4 exome AF: 0.105 AC: 153074 AN: 1461772 Hom.: 9154 Cov.: 39 AF XY: 0.103 AC XY: 74727 AN XY: 727204

Gnomad4 AFR exome AF: 0.0203

Gnomad4 AMR exome AF: 0.0648

Gnomad4 ASJ exome AF: 0.138

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0320

Gnomad4 FIN exome AF: 0.0482

Gnomad4 NFE exome AF: 0.120

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.0764 AC: 11627 AN: 152252 Hom.: 595 Cov.: 32 AF XY: 0.0721 AC XY: 5367 AN XY: 74450

Gnomad4 AFR AF: 0.0224

Gnomad4 AMR AF: 0.0926

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0270

Gnomad4 FIN AF: 0.0419

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.0951

Alfa AF: 0.0935 Hom.: 196

Bravo AF: 0.0794

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -

Osteogenesis imperfecta Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Ehlers-Danlos syndrome, arthrochalasia type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Osteogenesis imperfecta type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	15
Dann	Benign	0.81

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: rs17639446; hg19: chr17-48273903; COSMIC: COSV56806929; COSMIC: COSV56806929;