17-50188134-C-T

Position:

chr17-50188134-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000088.4(COL1A1):c.3223G>A(p.Ala1075Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,566,350 control chromosomes in the GnomAD database, including 337 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 80 hom., cov: 32)

Exomes 𝑓: 0.017 ( 257 hom. )

Consequence

COL1A1
NM_000088.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.54

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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=0.021361917).

BP6

Variant 17-50188134-C-T is Benign according to our data. Variant chr17-50188134-C-T is described in ClinVar as [Benign]. Clinvar id is 379433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188134-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL1A1	NM_000088.4 linkuse as main transcript	c.3223G>A	p.Ala1075Thr	missense_variant	44/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2 linkuse as main transcript	c.3025G>A	p.Ala1009Thr	missense_variant	41/48		XP_011522643.1
COL1A1	XM_005257058.5 linkuse as main transcript	c.2953G>A	p.Ala985Thr	missense_variant	42/49		XP_005257115.2
COL1A1	XM_005257059.5 linkuse as main transcript	c.2305G>A	p.Ala769Thr	missense_variant	31/38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
COL1A1	ENST00000225964.10 linkuse as main transcript	c.3223G>A	p.Ala1075Thr	missense_variant	44/51	1	NM_000088.4	ENSP00000225964	P1
COL1A1	ENST00000486572.1 linkuse as main transcript	n.421G>A		non_coding_transcript_exon_variant	1/2	3
COL1A1	ENST00000511732.1 linkuse as main transcript	n.547G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.0256

AC:

3890

AN:

151986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0542

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0116

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00436

Gnomad FIN

AF:

0.0244

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0166

Gnomad OTH

AF:

0.0172

GnomAD4 exome

AF:

0.0168

AC:

23769

AN:

1414248

Hom.:

257

Cov.:

AF XY:

0.0163

AC XY:

11418

AN XY:

699644

show subpopulations

Gnomad4 AFR exome

AF:

0.0576

Gnomad4 AMR exome

AF:

0.00856

Gnomad4 ASJ exome

AF:

0.00817

Gnomad4 EAS exome

AF:

0.0000270

Gnomad4 SAS exome

AF:

0.00459

Gnomad4 FIN exome

AF:

0.0221

Gnomad4 NFE exome

AF:

0.0173

Gnomad4 OTH exome

AF:

0.0174

GnomAD4 genome

AF:

0.0256

AC:

3893

AN:

152102

Hom.:

Cov.:

AF XY:

0.0253

AC XY:

1885

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0541

Gnomad4 AMR

AF:

0.0116

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00436

Gnomad4 FIN

AF:

0.0244

Gnomad4 NFE

AF:

0.0166

Gnomad4 OTH

AF:

0.0170

Alfa

AF:

0.0177

Hom.:

Bravo

AF:

0.0262

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 22, 2016

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. -

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

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Jan 17, 2023

This variant is present in gnomAD (Highest reported MAF: 5.4% [2240/41362], and in numerous homozygotes; https://gnomad.broadinstitute.org/variant/17-50188134-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID: 379433). In summary, this variant is classified as benign. -

Osteogenesis imperfecta type I

Benign:1

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

0.082

BayesDel_noAF

Benign

-0.34

CADD

Benign

MetaRNN

Benign

0.021

Sift4G

Benign

0.46

Vest4

0.44

gMVP

0.60

Splicing

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