rs2696247

Variant names:

• chr17-50192542-A-G
• rs2696247
• NM_000088.4:c.1930-14T>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.1930-14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,613,782 control chromosomes in the GnomAD database, including 19,716 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1707 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18009 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0100

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=-0.8).
• BP6: Variant 17-50192542-A-G is Benign according to our data. Variant chr17-50192542-A-G is described in ClinVar as [Benign]. Clinvar id is 254946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50192542-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.1930-14T>C		intron_variant	Intron 28 of 50	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.1732-14T>C		intron_variant	Intron 25 of 47		XP_011522643.1
COL1A1	XM_005257058.5	c.1930-14T>C		intron_variant	Intron 28 of 48		XP_005257115.2
COL1A1	XM_005257059.5	c.1012-14T>C		intron_variant	Intron 15 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.1930-14T>C		intron_variant	Intron 28 of 50	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000476387.1	n.279-14T>C		intron_variant	Intron 4 of 8	2
COL1A1	ENST00000504289.1	n.-103T>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21422 AN: 152034 Hom.: 1703 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.152

GnomAD3 exomes AF: 0.171 AC: 42946 AN: 251156 Hom.: 4326 AF XY: 0.176 AC XY: 23830 AN XY: 135754

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.346

Gnomad SAS exome AF: 0.271

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.149 AC: 217585 AN: 1461630 Hom.: 18009 Cov.: 36 AF XY: 0.153 AC XY: 111269 AN XY: 727124

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.153

Gnomad4 ASJ exome AF: 0.145

Gnomad4 EAS exome AF: 0.326

Gnomad4 SAS exome AF: 0.269

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.141 AC: 21436 AN: 152152 Hom.: 1707 Cov.: 32 AF XY: 0.145 AC XY: 10753 AN XY: 74382

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.144

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.347

Gnomad4 SAS AF: 0.260

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.154

Alfa AF: 0.144 Hom.: 1043

Bravo AF: 0.138

Asia WGS AF: 0.303 AC: 1051 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 23, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 05, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Infantile cortical hyperostosis Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.9
DANN	Benign	0.84

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

Other links and lift over

dbSNP: rs2696247; hg19: chr17-48269903; COSMIC: COSV56802824; COSMIC: COSV56802824;