chr17-50194072-A-G

Variant names:

• chr17-50194072-A-G
• rs1007086
• NM_000088.4:c.1669-31T>C

Variant summary

Our verdict is Benign. The variant received -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 (★★). There are indicators that this mutation may affect the branch point..

• 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:3
• Conservation: PhyloP100: 2.79
• Publications: 24 publications found

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]

COL1A1 Gene-Disease associations (from GenCC):

• Caffey disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, arthrochalasia type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• osteogenesis imperfecta type 1

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• osteogenesis imperfecta type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen
• Ehlers-Danlos syndrome, classic type, 1

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ehlers-Danlos/osteogenesis imperfecta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• high bone mass osteogenesis imperfecta

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. 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 VariationId 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 rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.1669-31T>C		intron_variant	Intron 24 of 50	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.1471-31T>C		intron_variant	Intron 21 of 47		XP_011522643.1
COL1A1	XM_005257058.5	c.1669-31T>C		intron_variant	Intron 24 of 48		XP_005257115.2
COL1A1	XM_005257059.5	c.958-1379T>C		intron_variant	Intron 14 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.1669-31T>C		intron_variant	Intron 24 of 50	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000471344.1	n.670T>C		non_coding_transcript_exon_variant	Exon 8 of 8	2
COL1A1	ENST00000463440.1	n.59-31T>C		intron_variant	Intron 2 of 2	2
COL1A1	ENST00000476387.1	n.-14T>C		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

GnomAD2 exomes AF: 0.663 AC: 166486 AN: 251098 AF XY: 0.661

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 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

African (AFR) AF: 0.507 AC: 16941 AN: 33410

American (AMR) AF: 0.722 AC: 32306 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.725 AC: 18925 AN: 26116

East Asian (EAS) AF: 0.540 AC: 21449 AN: 39692

South Asian (SAS) AF: 0.554 AC: 47708 AN: 86190

European-Finnish (FIN) AF: 0.724 AC: 38623 AN: 53364

Middle Eastern (MID) AF: 0.665 AC: 3831 AN: 5760

European-Non Finnish (NFE) AF: 0.700 AC: 776843 AN: 1109268

Other (OTH) AF: 0.672 AC: 40496 AN: 60294

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

African (AFR) AF: 0.516 AC: 21332 AN: 41304

American (AMR) AF: 0.705 AC: 10742 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2530 AN: 3468

East Asian (EAS) AF: 0.530 AC: 2716 AN: 5122

South Asian (SAS) AF: 0.569 AC: 2718 AN: 4774

European-Finnish (FIN) AF: 0.740 AC: 7798 AN: 10544

Middle Eastern (MID) AF: 0.668 AC: 195 AN: 292

European-Non Finnish (NFE) AF: 0.699 AC: 47408 AN: 67844

Other (OTH) AF: 0.672 AC: 1415 AN: 2106

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

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. -

not specified Benign:1

Jul 07, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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	-0.77
CADD	Benign	16
DANN	Benign	0.81
PhyloP100		2.8
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1007086; hg19: chr17-48271433; COSMIC: COSV56806184; COSMIC: COSV56806184;