rs1007086

chr17-50194072-A-Gchr17-50194072-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.1669-31T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 1,610,422 control chromosomes in the GnomAD database, including 375,399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (32010 hom., cov: 29)
  • Exomes 𝑓: 0.68 (343389 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.79

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 17-50194072-A-G is Benign according to our data. Variant chr17-50194072-A-G is described in ClinVar as [Benign]. Clinvar id is 674803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.1669-31T>C		intron_variant		ENST00000225964.10
COL1A1	XM_005257058.5	c.1669-31T>C		intron_variant
COL1A1	XM_005257059.5	c.958-1379T>C		intron_variant
COL1A1	XM_011524341.2	c.1471-31T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.1669-31T>C		intron_variant		1	NM_000088.4	P1
COL1A1	ENST00000471344.1	n.670T>C		non_coding_transcript_exon_variant	8/8	2
COL1A1	ENST00000463440.1	n.59-31T>C		intron_variant, non_coding_transcript_variant		2
COL1A1	ENST00000476387.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97472 AN: 151486 Hom.: 31991 Cov.: 29

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.741

Gnomad AMR AF: 0.705

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.531

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.740

Gnomad MID AF: 0.651

Gnomad NFE AF: 0.699

Gnomad OTH AF: 0.672

GnomAD3 exomes AF: 0.663 AC: 166486 AN: 251098 Hom.: 56115 AF XY: 0.661 AC XY: 89726 AN XY: 135772

Gnomad AFR exome AF: 0.506

Gnomad AMR exome AF: 0.729

Gnomad ASJ exome AF: 0.721

Gnomad EAS exome AF: 0.539

Gnomad SAS exome AF: 0.553

Gnomad FIN exome AF: 0.726

Gnomad NFE exome AF: 0.696

Gnomad OTH exome AF: 0.698

GnomAD4 exome AF: 0.684 AC: 997122 AN: 1458816 Hom.: 343389 Cov.: 35 AF XY: 0.679 AC XY: 492862 AN XY: 725878

Gnomad4 AFR exome AF: 0.507

Gnomad4 AMR exome AF: 0.722

Gnomad4 ASJ exome AF: 0.725

Gnomad4 EAS exome AF: 0.540

Gnomad4 SAS exome AF: 0.554

Gnomad4 FIN exome AF: 0.724

Gnomad4 NFE exome AF: 0.700

Gnomad4 OTH exome AF: 0.672

GnomAD4 genome AF: 0.643 AC: 97528 AN: 151606 Hom.: 32010 Cov.: 29 AF XY: 0.644 AC XY: 47676 AN XY: 74066

Gnomad4 AFR AF: 0.516

Gnomad4 AMR AF: 0.705

Gnomad4 ASJ AF: 0.730

Gnomad4 EAS AF: 0.530

Gnomad4 SAS AF: 0.569

Gnomad4 FIN AF: 0.740

Gnomad4 NFE AF: 0.699

Gnomad4 OTH AF: 0.672

Alfa AF: 0.674 Hom.: 9741

Bravo AF: 0.638

Asia WGS AF: 0.544 AC: 1892 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 07, 2018

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	16
Dann	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1007086; hg19: chr17-48271433; COSMIC: COSV56806184; COSMIC: COSV56806184;