rs199626372

chr17-50197190-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1 PP2 BP4 BP6 BS2

The NM_000088.4(COL1A1):c.740C>T(p.Pro247Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,613,640 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 8.03

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 Likely_benign. Variant got -3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000088.4
• PP2: Missense variant where missense usually causes diseases, COL1A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.33784413).
• BP6: Variant 17-50197190-G-A is Benign according to our data. Variant chr17-50197190-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287981.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}. Variant chr17-50197190-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.740C>T	p.Pro247Leu	missense_variant	10/51	ENST00000225964.10
COL1A1	XM_011524341.2	c.740C>T	p.Pro247Leu	missense_variant	10/48
COL1A1	XM_005257058.5	c.740C>T	p.Pro247Leu	missense_variant	10/49
COL1A1	XM_005257059.5	c.740C>T	p.Pro247Leu	missense_variant	10/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.740C>T	p.Pro247Leu	missense_variant	10/51	1	NM_000088.4	P1
COL1A1	ENST00000495677.1	n.467C>T		non_coding_transcript_exon_variant	5/8	3

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251448 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000286 AC: 418 AN: 1461404 Hom.: 0 Cov.: 34 AF XY: 0.000279 AC XY: 203 AN XY: 727022

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000341

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74454

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000272 Hom.: 0

Bravo AF: 0.000363

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 31, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2021	Reported in two brothers from one Spanish family, one diagnosed with mild autosomal recessive osteogenesis imperfecta and the other diagnosed with mild Bruck syndrome (Puig-Hervas et al., 2012); however, this variant was also found in their unaffected father, and both brothers were also compound heterozygous for a splice site variant and a missense variant in the PLOD1 gene; Reported in ClinVar as a variant of uncertain significance but additional evidence is not available (ClinVar Variant ID# 287981; Landrum et al., 2016); Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat. Although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22689593, 25983617) -

Ehlers-Danlos syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 14, 2022

- -

COL1A1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2021

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.34	T
MetaSVM	Pathogenic	0.90	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.56
Sift	Benign	0.036	D
Sift4G	Uncertain	0.052	T
Vest4		0.39
MVP		0.85
MPC		0.57
ClinPred		0.22	T
GERP RS		4.9
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs199626372; hg19: chr17-48274551;