rs138078016

Positions:

chr17-50197979-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000088.4(COL1A1):c.612C>T(p.Pro204=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000802 in 1,614,056 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 6 hom. )

Consequence

COL1A1
NM_000088.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.509

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 17-50197979-G-A is Benign according to our data. Variant chr17-50197979-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 35926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50197979-G-A is described in Lovd as [Benign]. Variant chr17-50197979-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.509 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00436 (664/152182) while in subpopulation AFR AF= 0.0155 (643/41512). AF 95% confidence interval is 0.0145. There are 5 homozygotes in gnomad4. There are 317 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 664 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL1A1	NM_000088.4 linkuse as main transcript	c.612C>T	p.Pro204=	synonymous_variant	8/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2 linkuse as main transcript	c.612C>T	p.Pro204=	synonymous_variant	8/48		XP_011522643.1
COL1A1	XM_005257058.5 linkuse as main transcript	c.612C>T	p.Pro204=	synonymous_variant	8/49		XP_005257115.2
COL1A1	XM_005257059.5 linkuse as main transcript	c.612C>T	p.Pro204=	synonymous_variant	8/38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10 linkuse as main transcript	c.612C>T	p.Pro204=	synonymous_variant	8/51	1	NM_000088.4	ENSP00000225964	P1
COL1A1	ENST00000495677.1 linkuse as main transcript	n.339C>T		non_coding_transcript_exon_variant	3/8	3

Frequencies

GnomAD3 genomes

AF:

0.00436

AC:

663

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00115

AC:

289

AN:

250818

Hom.:

AF XY:

0.000839

AC XY:

114

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.0156

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000431

AC:

630

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000360

AC XY:

262

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0151

Gnomad4 AMR exome

AF:

0.000805

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00101

GnomAD4 genome

AF:

0.00436

AC:

664

AN:

152182

Hom.:

Cov.:

AF XY:

0.00426

AC XY:

317

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0155

Gnomad4 AMR

AF:

0.000915

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:

0.00284

Alfa

AF:

0.00244

Hom.:

Bravo

AF:

0.00496

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Osteogenesis imperfecta

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Mar 10, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 18, 2023	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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