rs1555575889

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr17-50201513-T-A
• chr17-50201513-T-C
• chr17-50201513-T-G

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>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• 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 112 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-A is Pathogenic according to our data. Variant chr17-50201513-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2084407.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000088.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	NM_000088.4	MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 51	NP_000079.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	ENST00000225964.10	TSL:1 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 51	ENSP00000225964.6
	COL1A1	ENST00000861334.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 51	ENSP00000531393.1
	COL1A1	ENST00000861339.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 51	ENSP00000531398.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Osteogenesis imperfecta type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Benign	0.96
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.90	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		-0.054	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;