chr17-50201513-T-G

Variant names:

• chr17-50201513-T-G
• rs1555575889
• NM_000088.4:c.1A>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000088.4(COL1A1):​c.1A>C​(p.Met1?) variant causes a initiator codon 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 initiator_codon
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.84
• Publications: 1 publications found

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]

TILAM (HGNC:52795): (long intergenic non-protein coding RNA 1969)

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 110 pathogenic variants. Next in-frame start position is after 181 codons. Genomic position: 50198435. Lost 0.123 part of the original CDS.
• PS1: Another start lost variant in NM_000088.4 (COL1A1) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-50201513-T-G is Pathogenic according to our data. Variant chr17-50201513-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1457923.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000474644.1	n.120A>C		non_coding_transcript_exon_variant	Exon 1 of 4	3
TILAM	ENST00000509943.2	n.59+1579T>G		intron_variant	Intron 1 of 6	3
TILAM	ENST00000832079.1	n.155+267T>G		intron_variant	Intron 1 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458680 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725720

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4316

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111858

Other (OTH) AF: 0.00 AC: 0 AN: 60226

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type I Pathogenic:1

Oct 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the COL1A1 mRNA. The next in-frame methionine is located at codon 181. This variant is not present in population databases (ExAC no frequency). Disruption of the initiator codon has been observed in individuals with osteogenesis imperfecta (PMID: 23529829, 25696019, 31447884; Invitae). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Benign	0.95
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.56	D
PhyloP100		7.8
PROVEAN	Benign	-1.2	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.050	T
Vest4		0.90
MutPred		0.89		Loss of disorder (P = 0.143);
MVP		0.99
ClinPred		0.99	D
GERP RS		5.0
PromoterAI		-0.035	Neutral
gMVP		0.81
Mutation Taster		=1/199	disease causing

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

Other links and lift over

dbSNP: rs1555575889; hg19: chr17-48278874;