17-50199907-A-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBP6BS2

The NM_000088.4(COL1A1):c.144T>A(p.His48Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

COL1A1
NM_000088.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.60

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:

ENSG00000249406 (HGNC:52795): (long intergenic non-protein coding RNA 1969)

ENSG00000249406 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a propeptide N-terminal propeptide (size 138) in uniprot entity CO1A1_HUMAN there are 22 pathogenic changes around while only 3 benign (88%) in NM_000088.4

PP2

Missense variant in the COL1A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 368 curated pathogenic missense variants (we use a threshold of 10). The gene has 98 curated benign missense variants. Gene score misZ: 3.5319 (above the threshold of 3.09). Trascript score misZ: 5.7733 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.058568).

BP6

Variant 17-50199907-A-T is Benign according to our data. Variant chr17-50199907-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 662041.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=4}.

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4 link	c.144T>A	p.His48Gln	missense_variant	Exon 2 of 51	ENST00000225964.10	NP_000079.2	P02452
COL1A1	XM_011524341.2 link	c.144T>A	p.His48Gln	missense_variant	Exon 2 of 48		XP_011522643.1
COL1A1	XM_005257058.5 link	c.144T>A	p.His48Gln	missense_variant	Exon 2 of 49		XP_005257115.2
COL1A1	XM_005257059.5 link	c.144T>A	p.His48Gln	missense_variant	Exon 2 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL1A1	ENST00000225964.10 link	c.144T>A	p.His48Gln	missense_variant	Exon 2 of 51	1	NM_000088.4	ENSP00000225964.6	P02452
COL1A1	ENST00000507689.1 link	c.198T>A	p.His66Gln	missense_variant	Exon 1 of 4	2		ENSP00000460459.1	I3L3H7
COL1A1	ENST00000474644.1 link	n.263T>A		non_coding_transcript_exon_variant	Exon 2 of 4	3
ENSG00000249406	ENST00000509943.2 link	n.32A>T		non_coding_transcript_exon_variant	Exon 1 of 7	3

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251338

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000118

AC:

173

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000145

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000158

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

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

Sep 26, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD) -

Jun 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COL1A1 c.144T>A; p.His48Gln variant (rs374065372) is reported in the literature in an individual affected with thoracic aortic aneurysm (Salmasi 2022). This variant is reported in ClinVar (Variation ID: 662041) and is found in the non-Finnish European population with an allele frequency of 0.02% (24/129,100 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.123). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Salmasi MY et al. Determining the genetic contribution in patients with non-syndromic ascending thoracic aortic aneurysms: Correlation with findings from computational pathology. Int J Cardiol. 2022 Nov 1;366:1-9. PMID: 35830949. -

Cardiovascular phenotype

Uncertain:1

May 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H48Q variant (also known as c.144T>A), located in coding exon 2 of the COL1A1 gene, results from a T to A substitution at nucleotide position 144. The histidine at codon 48 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Osteogenesis imperfecta

Benign:1

Apr 22, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

Apr 22, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta type I

Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.62

CADD

Benign

6.2

DANN

Benign

0.92

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.37

.;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.059

T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.52

N;.

REVEL

Benign

0.12

Sift

Benign

0.59

T;.

Sift4G

Benign

0.64

T;T

Vest4

0.13

MutPred

0.54

Loss of sheet (P = 0.0315);.;

MVP

0.43

MPC

0.56

ClinPred

0.035

GERP RS

-11

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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