rs193922146

Positions:

• chr17-50190941-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000225964.10(COL1A1):​c.2236-17C>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 0.000929 in 1,610,566 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00089 (6 hom.)
• Consequence: COL1A1 ENST00000225964.10 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.812

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 17-50190941-G-C is Benign according to our data. Variant chr17-50190941-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 35909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50190941-G-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 196 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.2236-17C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000225964.10	NP_000079.2
COL1A1	XM_005257058.5	c.2236-17C>G		splice_polypyrimidine_tract_variant, intron_variant			XP_005257115.2
COL1A1	XM_005257059.5	c.1318-17C>G		splice_polypyrimidine_tract_variant, intron_variant			XP_005257116.2
COL1A1	XM_011524341.2	c.2038-17C>G		splice_polypyrimidine_tract_variant, intron_variant			XP_011522643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.2236-17C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000088.4	ENSP00000225964	P1
COL1A1	ENST00000476387.1	n.585-17C>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2
COL1A1	ENST00000494334.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152086 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00105 AC: 264 AN: 250740 Hom.: 0 AF XY: 0.000944 AC XY: 128 AN XY: 135598

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00466

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000892 AC: 1301 AN: 1458480 Hom.: 6 Cov.: 33 AF XY: 0.000966 AC XY: 701 AN XY: 725740

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00437

Gnomad4 NFE exome AF: 0.000892

Gnomad4 OTH exome AF: 0.000713

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152086 Hom.: 0 Cov.: 31 AF XY: 0.00159 AC XY: 118 AN XY: 74310

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00754

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.000958

Alfa AF: 0.00230 Hom.: 0

Bravo AF: 0.000710

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	COL1A1: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 03, 2023

Variant summary: COL1A1 c.2236-17C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0011 in 250740 control chromosomes (gnomAD). The observed variant frequency is approximately 37 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A1 causing Osteogenesis Imperfecta phenotype (2.8e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2236-17C>G in individuals affected with Osteogenesis Imperfecta and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Osteogenesis imperfecta type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.0
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs193922146; hg19: chr17-48268302;