rs1555575889

chr17-50201513-T-Cchr17-50201513-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000088.4(COL1A1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: COL1A1 NM_000088.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.84

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000088.4 (COL1A1) was described as [Pathogenic] in ClinVar as 567004
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-50201513-T-C is Pathogenic according to our data. Variant chr17-50201513-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 526867.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-50201513-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.1A>G	p.Met1?	start_lost	1/51	ENST00000225964.10
COL1A1	XM_011524341.2	c.1A>G	p.Met1?	start_lost	1/48
COL1A1	XM_005257058.5	c.1A>G	p.Met1?	start_lost	1/49
COL1A1	XM_005257059.5	c.1A>G	p.Met1?	start_lost	1/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.1A>G	p.Met1?	start_lost	1/51	1	NM_000088.4	P1
	ENST00000509943.2	n.59+1579T>C		intron_variant, non_coding_transcript_variant		3
COL1A1	ENST00000474644.1	n.120A>G		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458680 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725720

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Osteogenesis imperfecta type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 30, 2020

For these reasons, this variant has been classified as Pathogenic. This variant has been reported in several individuals affected with osteogenesis imperfecta, type 1 (PMID: 27509835).  Additionally, other nucleotide changes at the COL1A1 initiator codon (c.2T>G and c.2T>C) have also been reported in individuals affected with osteogenesis imperfecta, type 1 (PMID: 25696019, 23529829). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the COL1A1 mRNA. The next in-frame methionine is located at codon 181. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.77	D
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Vest4		0.95
MutPred		0.85		Loss of loop (P = 0.0986);
MVP		0.99
ClinPred		0.99	D
GERP RS		5.0
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1555575889; hg19: chr17-48278874;