rs2586488

Positions:

• chr17-50188065-A-G
• chr17-50188065-A-T

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.3261+31T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.682 in 1,612,540 control chromosomes in the GnomAD database, including 376,972 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33444 hom., cov: 33)
  • Exomes 𝑓: 0.68 (343528 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.761

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=-0.84).
• BP6: Variant 17-50188065-A-G is Benign according to our data. Variant chr17-50188065-A-G is described in ClinVar as [Benign]. Clinvar id is 674808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.3261+31T>C		intron_variant		ENST00000225964.10
COL1A1	XM_005257058.5	c.2991+31T>C		intron_variant
COL1A1	XM_005257059.5	c.2343+31T>C		intron_variant
COL1A1	XM_011524341.2	c.3063+31T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.3261+31T>C		intron_variant		1	NM_000088.4	P1
COL1A1	ENST00000511732.1	n.616T>C		non_coding_transcript_exon_variant	2/2	2
COL1A1	ENST00000486572.1	n.459+31T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.660 AC: 100302 AN: 152006 Hom.: 33421 Cov.: 33

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.836

Gnomad AMR AF: 0.717

Gnomad ASJ AF: 0.748

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.615

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.684

GnomAD3 exomes AF: 0.670 AC: 166345 AN: 248426 Hom.: 56155 AF XY: 0.668 AC XY: 89834 AN XY: 134404

Gnomad AFR exome AF: 0.575

Gnomad AMR exome AF: 0.724

Gnomad ASJ exome AF: 0.744

Gnomad EAS exome AF: 0.527

Gnomad SAS exome AF: 0.604

Gnomad FIN exome AF: 0.702

Gnomad NFE exome AF: 0.693

Gnomad OTH exome AF: 0.707

GnomAD4 exome AF: 0.684 AC: 999503 AN: 1460416 Hom.: 343528 Cov.: 43 AF XY: 0.681 AC XY: 494916 AN XY: 726378

Gnomad4 AFR exome AF: 0.581

Gnomad4 AMR exome AF: 0.722

Gnomad4 ASJ exome AF: 0.745

Gnomad4 EAS exome AF: 0.556

Gnomad4 SAS exome AF: 0.604

Gnomad4 FIN exome AF: 0.701

Gnomad4 NFE exome AF: 0.695

Gnomad4 OTH exome AF: 0.681

GnomAD4 genome AF: 0.660 AC: 100370 AN: 152124 Hom.: 33444 Cov.: 33 AF XY: 0.660 AC XY: 49082 AN XY: 74356

Gnomad4 AFR AF: 0.581

Gnomad4 AMR AF: 0.717

Gnomad4 ASJ AF: 0.748

Gnomad4 EAS AF: 0.531

Gnomad4 SAS AF: 0.615

Gnomad4 FIN AF: 0.716

Gnomad4 NFE AF: 0.691

Gnomad4 OTH AF: 0.683

Alfa AF: 0.690 Hom.: 59444

Bravo AF: 0.661

Asia WGS AF: 0.556 AC: 1935 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type III Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Ehlers-Danlos syndrome, arthrochalasia type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Osteogenesis imperfecta with normal sclerae, dominant form Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Osteogenesis imperfecta, perinatal lethal Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Osteogenesis imperfecta type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.42

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: rs2586488; hg19: chr17-48265426; COSMIC: COSV56803091; COSMIC: COSV56803091;