rs1800217

Positions:

• chr17-50188114-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000088.4(COL1A1):​c.3243T>C​(p.Val1081=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00687 in 1,583,936 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (74 hom.)
• Consequence: COL1A1 NM_000088.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 3.44

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 17-50188114-A-G is Benign according to our data. Variant chr17-50188114-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 197496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188114-A-G is described in Lovd as [Likely_benign]. Variant chr17-50188114-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00484 (737/152270) while in subpopulation SAS AF= 0.00994 (48/4830). AF 95% confidence interval is 0.0077. There are 6 homozygotes in gnomad4. There are 347 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 737 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.3243T>C	p.Val1081=	synonymous_variant	44/51	ENST00000225964.10
COL1A1	XM_011524341.2	c.3045T>C	p.Val1015=	synonymous_variant	41/48
COL1A1	XM_005257058.5	c.2973T>C	p.Val991=	synonymous_variant	42/49
COL1A1	XM_005257059.5	c.2325T>C	p.Val775=	synonymous_variant	31/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.3243T>C	p.Val1081=	synonymous_variant	44/51	1	NM_000088.4	P1
COL1A1	ENST00000486572.1	n.441T>C		non_coding_transcript_exon_variant	1/2	3
COL1A1	ENST00000511732.1	n.567T>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00484 AC: 737 AN: 152154 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00993

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00725

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00615 AC: 1203 AN: 195556 Hom.: 14 AF XY: 0.00710 AC XY: 751 AN XY: 105766

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0136

Gnomad FIN exome AF: 0.00234

Gnomad NFE exome AF: 0.00831

Gnomad OTH exome AF: 0.00529

GnomAD4 exome AF: 0.00708 AC: 10138 AN: 1431666 Hom.: 74 Cov.: 36 AF XY: 0.00723 AC XY: 5129 AN XY: 709846

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0132

Gnomad4 FIN exome AF: 0.00288

Gnomad4 NFE exome AF: 0.00751

Gnomad4 OTH exome AF: 0.00722

GnomAD4 genome AF: 0.00484 AC: 737 AN: 152270 Hom.: 6 Cov.: 32 AF XY: 0.00466 AC XY: 347 AN XY: 74458

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.00457

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00994

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00725

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00592 Hom.: 3

Bravo AF: 0.00487

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 22, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2017	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 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 09, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	COL1A1: BP4, BP7, BS1, BS2 -

Infantile cortical hyperostosis;C0023931:Osteogenesis imperfecta type I;C0029456:Osteoporosis;C0268358:Osteogenesis imperfecta, perinatal lethal;C0268362:Osteogenesis imperfecta type III;C0268363:Osteogenesis imperfecta with normal sclerae, dominant form;C4551623:Ehlers-Danlos syndrome, arthrochalasia type;C5436842:Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 24, 2021

- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 19, 2022

- -

Ehlers-Danlos syndrome, arthrochalasia type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Infantile cortical hyperostosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Osteogenesis imperfecta type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	3.2
DANN	Benign	0.78

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: rs1800217; hg19: chr17-48265475;