17-50197978-G-C

Position:

• chr17-50197978-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM1 PP2 BP4_Strong BS1 BS2

The NM_000088.4(COL1A1):​c.613C>G​(p.Pro205Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00497 in 1,614,078 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (26 hom.)
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:18
• Conservation: PhyloP100: 6.40

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 -9 ACMG points.

• PM1: In a compositionally_biased_region Pro residues (size 43) in uniprot entity CO1A1_HUMAN there are 83 pathogenic changes around while only 2 benign (98%) in NM_000088.4
• 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). The gene has 368 curated pathogenic missense variants (we use a threshold of 10). The gene has 98 curated benign missense variants. GenCC has associacion of the 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=0.026518553).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00334 (508/152232) while in subpopulation NFE AF= 0.00495 (337/68014). AF 95% confidence interval is 0.00452. There are 1 homozygotes in gnomad4. There are 241 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 508 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.613C>G	p.Pro205Ala	missense_variant	8/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.613C>G	p.Pro205Ala	missense_variant	8/48		XP_011522643.1
COL1A1	XM_005257058.5	c.613C>G	p.Pro205Ala	missense_variant	8/49		XP_005257115.2
COL1A1	XM_005257059.5	c.613C>G	p.Pro205Ala	missense_variant	8/38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.613C>G	p.Pro205Ala	missense_variant	8/51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000495677.1	n.340C>G		non_coding_transcript_exon_variant	3/8	3

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 509 AN: 152114 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00495

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00334 AC: 838 AN: 250772 Hom.: 6 AF XY: 0.00371 AC XY: 504 AN XY: 135864

Gnomad AFR exome AF: 0.00112

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00428

Gnomad FIN exome AF: 0.00231

Gnomad NFE exome AF: 0.00509

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00514 AC: 7513 AN: 1461846 Hom.: 26 Cov.: 32 AF XY: 0.00513 AC XY: 3734 AN XY: 727230

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00451

Gnomad4 FIN exome AF: 0.00213

Gnomad4 NFE exome AF: 0.00592

Gnomad4 OTH exome AF: 0.00455

GnomAD4 genome AF: 0.00334 AC: 508 AN: 152232 Hom.: 1 Cov.: 32 AF XY: 0.00324 AC XY: 241 AN XY: 74428

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00349

Gnomad4 NFE AF: 0.00495

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00452 Hom.: 2

Bravo AF: 0.00299

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00358 AC: 434

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00551

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:18

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:8

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	COL1A1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 02, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 29, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2018	This variant is associated with the following publications: (PMID: 30715774, 27884173, 8079666) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Osteogenesis imperfecta Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	GenePathDx, GenePath diagnostics	Jun 01, 2016	7 years old male child, a suspected case of osteogenesis imperfecta. History of recurrent long bone fractures after trivial falls. Sclera and dentition are apparently normal. No family history of similar complaints. Next generation DNA sequencing peripheral blood sample has revealed the presence of the heterozygous variant c.613C>G in the COL1A1 gene. This variant is being called a “variant of unknown significance” based on available evidence in the databases and in silico mutation prediction methods. Kindly correlate with the family history and clinical details. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jan 22, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jan 05, 2024	- -

not specified Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Infantile cortical hyperostosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Connective tissue disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 11, 2022

- -

Ehlers-Danlos syndrome, arthrochalasia type Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2019

This alteration is classified as likely 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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.039
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	21
DANN	Benign	0.94
Eigen	Benign	-0.064
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.027	T
MetaSVM	Uncertain	0.43	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.60
Sift	Benign	0.24	T
Sift4G	Benign	0.092	T
Vest4		0.75
MVP		0.96
MPC		0.54
ClinPred		0.080	T
GERP RS		3.4
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs72667032; hg19: chr17-48275339;