rs199911681

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.3849C>A(p.Asn1283Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,614,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 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 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

COL1A1
NM_000088.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.855

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 -6 ACMG points.

PM1

In a disulfide_bond (size 32) in uniprot entity CO1A1_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) 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=0.065333426).

BP6

Variant 17-50186473-G-T is Benign according to our data. Variant chr17-50186473-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 456779.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4 link	c.3849C>A	p.Asn1283Lys	missense_variant	Exon 49 of 51	ENST00000225964.10	NP_000079.2	P02452
COL1A1	XM_011524341.2 link	c.3651C>A	p.Asn1217Lys	missense_variant	Exon 46 of 48		XP_011522643.1
COL1A1	XM_005257058.5 link	c.3579C>A	p.Asn1193Lys	missense_variant	Exon 47 of 49		XP_005257115.2
COL1A1	XM_005257059.5 link	c.2931C>A	p.Asn977Lys	missense_variant	Exon 36 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10 link	c.3849C>A	p.Asn1283Lys	missense_variant	Exon 49 of 51	1	NM_000088.4	ENSP00000225964.6		P02452
COL1A1	ENST00000510710.3 link	n.518C>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251480

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000230

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000329

Hom.:

Bravo

AF:

0.000325

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Jan 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N1283K variant (also known as c.3849C>A), located in coding exon 49 of the COL1A1 gene, results from a C to A substitution at nucleotide position 3849. The asparagine at codon 1283 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well 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. -

not provided

Benign:1

Mar 23, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta type I

Benign:1

Dec 14, 2024

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

Uncertain

0.37

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Benign

0.96

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.77

M_CAP

Benign

0.031

MetaRNN

Benign

0.065

MetaSVM

Benign

-0.94

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.80

REVEL

Benign

0.20

Sift

Benign

0.12

Sift4G

Benign

0.55

Vest4

0.57

MutPred

0.65

Gain of methylation at N1283 (P = 0.0051);

MVP

0.79

MPC

0.65

ClinPred

0.022

GERP RS

3.5

gMVP

0.58

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

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