rs41316667

Positions:

Variant summary

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

The NM_000088.4(COL1A1):c.1821C>T(p.Val607Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,613,670 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 12 hom., cov: 32)

Exomes 𝑓: 0.00079 ( 17 hom. )

Consequence

COL1A1
NM_000088.4 splice_region, synonymous

Scores

Splicing: ADA: 0.0002680

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.87

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:

COL1A1 (HGNC:):

COL1A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 17-50192994-G-A is Benign according to our data. Variant chr17-50192994-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 286349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50192994-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.87 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00696 (1057/151916) while in subpopulation AFR AF= 0.0237 (983/41426). AF 95% confidence interval is 0.0225. There are 12 homozygotes in gnomad4. There are 518 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1057 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4 linkuse as main transcript	c.1821C>T	p.Val607Val	splice_region_variant, synonymous_variant	26/51	ENST00000225964.10	NP_000079.2	P02452
COL1A1	XM_011524341.2 linkuse as main transcript	c.1623C>T	p.Val541Val	splice_region_variant, synonymous_variant	23/48		XP_011522643.1
COL1A1	XM_005257058.5 linkuse as main transcript	c.1821C>T	p.Val607Val	splice_region_variant, synonymous_variant	26/49		XP_005257115.2
COL1A1	XM_005257059.5 linkuse as main transcript	c.958-301C>T		intron_variant			XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10 linkuse as main transcript	c.1821C>T	p.Val607Val	splice_region_variant, synonymous_variant	26/51	1	NM_000088.4	ENSP00000225964.6		P02452
COL1A1	ENST00000476387.1 linkuse as main transcript	n.170C>T		splice_region_variant, non_coding_transcript_exon_variant	2/9	2

Frequencies

GnomAD3 genomes

AF:

0.00694

AC:

1054

AN:

151798

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0237

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00289

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:

0.000221

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.00192

AC:

482

AN:

250704

Hom.:

AF XY:

0.00130

AC XY:

176

AN XY:

135498

show subpopulations

Gnomad AFR exome

AF:

0.0258

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000786

AC:

1149

AN:

1461754

Hom.:

Cov.:

AF XY:

0.000650

AC XY:

473

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.0273

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000800

Gnomad4 OTH exome

AF:

0.00136

GnomAD4 genome

AF:

0.00696

AC:

1057

AN:

151916

Hom.:

Cov.:

AF XY:

0.00697

AC XY:

518

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.0237

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00711

Alfa

AF:

0.000918

Hom.:

Bravo

AF:

0.00832

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 27, 2024	- -

Osteogenesis imperfecta

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Sep 24, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this 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

Fulgent Genetics, Fulgent Genetics

Aug 02, 2021

- -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 24, 2021

- -

Ehlers-Danlos syndrome, arthrochalasia type

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 20, 2023

- -

Infantile cortical hyperostosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 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 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

5.0

DANN

Benign

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00027

dbscSNV1_RF

Benign

0.038

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