17-50188799-CAGAGAG-CAGAG

Variant names:

• chr17-50188799-CAG-C
• rs138425306
• NM_000088.4:c.3046-6_3046-5delCT

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000088.4(COL1A1):​c.3046-6_3046-5delCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000525 in 148,668 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL1A1 NM_000088.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.14

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 -12 ACMG points.

• BP6: Variant 17-50188799-CAG-C is Benign according to our data. Variant chr17-50188799-CAG-C is described in ClinVar as [Benign]. Clinvar id is 701827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188799-CAG-C is described in Lovd as [Benign]. Variant chr17-50188799-CAG-C is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 78 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.3046-6_3046-5delCT		splice_region_variant, intron_variant	Intron 41 of 50	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.2848-6_2848-5delCT		splice_region_variant, intron_variant	Intron 38 of 47		XP_011522643.1
COL1A1	XM_005257058.5	c.2776-6_2776-5delCT		splice_region_variant, intron_variant	Intron 39 of 48		XP_005257115.2
COL1A1	XM_005257059.5	c.2128-6_2128-5delCT		splice_region_variant, intron_variant	Intron 28 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.3046-6_3046-5delCT		splice_region_variant, intron_variant	Intron 41 of 50	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000486572.1	n.-247_-246delCT		upstream_gene_variant		3
COL1A1	ENST00000511732.1	n.-17_-16delCT		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.000525 AC: 78 AN: 148584 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000871

Gnomad ASJ AF: 0.000293

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000629

Gnomad OTH AF: 0.000978

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.0411 AC: 30109 AN: 732360 Hom.: 0 AF XY: 0.0411 AC XY: 14292 AN XY: 347486

Gnomad4 AFR exome AF: 0.0300

Gnomad4 AMR exome AF: 0.0404

Gnomad4 ASJ exome AF: 0.0614

Gnomad4 EAS exome AF: 0.0273

Gnomad4 SAS exome AF: 0.0672

Gnomad4 FIN exome AF: 0.0263

Gnomad4 NFE exome AF: 0.0413

Gnomad4 OTH exome AF: 0.0395

GnomAD4 genome AF: 0.000525 AC: 78 AN: 148668 Hom.: 0 Cov.: 32 AF XY: 0.000676 AC XY: 49 AN XY: 72508

Gnomad4 AFR AF: 0.0000488

Gnomad4 AMR AF: 0.000870

Gnomad4 ASJ AF: 0.000293

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00191

Gnomad4 NFE AF: 0.000630

Gnomad4 OTH AF: 0.000971

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta type I Benign:1

Oct 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs138425306; hg19: chr17-48266160;