rs199626372

Positions:

chr17-50197190-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4BP6BS2

The NM_000088.4(COL1A1):c.740C>T(p.Pro247Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,613,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

COL1A1
NM_000088.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 8.03

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a modified_residue 4-hydroxyproline (size 0) in uniprot entity CO1A1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000088.4

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL1A1. . Gene score misZ 3.5319 (greater than the threshold 3.09). Trascript score misZ 5.7733 (greater than threshold 3.09). GenCC has associacion of gene with Caffey disease, Ehlers-Danlos/osteogenesis imperfecta syndrome, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, Ehlers-Danlos syndrome, arthrochalasia type, osteogenesis imperfecta type 3, Ehlers-Danlos syndrome, classic type, 1, high bone mass osteogenesis imperfecta, osteogenesis imperfecta type 4, Ehlers-Danlos syndrome, classic type, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.33784413).

BP6

Variant 17-50197190-G-A is Benign according to our data. Variant chr17-50197190-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287981.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}. Variant chr17-50197190-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL1A1	NM_000088.4 linkuse as main transcript	c.740C>T	p.Pro247Leu	missense_variant	10/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2 linkuse as main transcript	c.740C>T	p.Pro247Leu	missense_variant	10/48		XP_011522643.1
COL1A1	XM_005257058.5 linkuse as main transcript	c.740C>T	p.Pro247Leu	missense_variant	10/49		XP_005257115.2
COL1A1	XM_005257059.5 linkuse as main transcript	c.740C>T	p.Pro247Leu	missense_variant	10/38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10 linkuse as main transcript	c.740C>T	p.Pro247Leu	missense_variant	10/51	1	NM_000088.4	ENSP00000225964	P1
COL1A1	ENST00000495677.1 linkuse as main transcript	n.467C>T		non_coding_transcript_exon_variant	5/8	3

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000163

AC:

AN:

251448

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000286

AC:

418

AN:

1461404

Hom.:

Cov.:

AF XY:

0.000279

AC XY:

203

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000341

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000355

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00229

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000272

Hom.:

Bravo

AF:

0.000363

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 31, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2024	Reported in two brothers from one Spanish family, one diagnosed with mild autosomal recessive osteogenesis imperfecta and the other diagnosed with mild Bruck syndrome; however, this variant was also found in their unaffected father, and both brothers were also compound heterozygous for a splice site variant and a missense variant in the PLOD1 gene (PMID: 22689593); Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat. Although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25983617, 22689593) -

Ehlers-Danlos syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 14, 2022

- -

COL1A1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2021

This alteration is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.83

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.34

MetaSVM

Pathogenic

0.90

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.56

Sift

Benign

0.036

Sift4G

Uncertain

0.052

Vest4

0.39

MVP

0.85

MPC

0.57

ClinPred

0.22

GERP RS

4.9

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over