chr17-50192994-G-A

Position:

• chr17-50192994-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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

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 (HGNC:):

ACMG classification

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	c.1821C>T	p.Val607Val	splice_region_variant, synonymous_variant	26/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.1623C>T	p.Val541Val	splice_region_variant, synonymous_variant	23/48		XP_011522643.1
COL1A1	XM_005257058.5	c.1821C>T	p.Val607Val	splice_region_variant, synonymous_variant	26/49		XP_005257115.2
COL1A1	XM_005257059.5	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	c.1821C>T	p.Val607Val	splice_region_variant, synonymous_variant	26/51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000476387.1	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.: 12 Cov.: 32

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.: 6 AF XY: 0.00130 AC XY: 176 AN XY: 135498

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.: 17 Cov.: 34 AF XY: 0.000650 AC XY: 473 AN XY: 727180

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.: 12 Cov.: 32 AF XY: 0.00697 AC XY: 518 AN XY: 74272

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.: 4

Bravo AF: 0.00832

Asia WGS AF: 0.00173 AC: 6 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

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

Other links and lift over

dbSNP: rs41316667; hg19: chr17-48270355; COSMIC: COSV104388048; COSMIC: COSV104388048;