rs138078016

chr17-50197979-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.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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.509

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High AC in GnomAd at 663 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.612C>T	p.Pro204=	synonymous_variant	8/51	ENST00000225964.10
COL1A1	XM_011524341.2	c.612C>T	p.Pro204=	synonymous_variant	8/48
COL1A1	XM_005257058.5	c.612C>T	p.Pro204=	synonymous_variant	8/49
COL1A1	XM_005257059.5	c.612C>T	p.Pro204=	synonymous_variant	8/38

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00436 AC: 663 AN: 152064 Hom.: 5 Cov.: 32

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.: 3 AF XY: 0.000839 AC XY: 114 AN XY: 135882

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.: 6 Cov.: 32 AF XY: 0.000360 AC XY: 262 AN XY: 727246

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.: 5 Cov.: 32 AF XY: 0.00426 AC XY: 317 AN XY: 74402

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.: 3

Bravo AF: 0.00496

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	-	- -

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 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

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	13
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

Other links and lift over

dbSNP: rs138078016; hg19: chr17-48275340;