rs1555575835

Variant names:

• chr17-50201406-C-G
• rs1555575835
• NM_000088.4:c.103+5G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-50201406-C-G
• chr17-50201406-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000088.4(COL1A1):​c.103+5G>C variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL1A1 NM_000088.4 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.59
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-50201406-C-G is Pathogenic according to our data. Variant chr17-50201406-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 836318.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.103+5G>C		splice_region_variant, intron_variant	Intron 1 of 50	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.103+5G>C		splice_region_variant, intron_variant	Intron 1 of 47		XP_011522643.1
COL1A1	XM_005257058.5	c.103+5G>C		splice_region_variant, intron_variant	Intron 1 of 48		XP_005257115.2
COL1A1	XM_005257059.5	c.103+5G>C		splice_region_variant, intron_variant	Intron 1 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.103+5G>C		splice_region_variant, intron_variant	Intron 1 of 50	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000474644.1	n.222+5G>C		splice_region_variant, intron_variant	Intron 1 of 3	3
TILAM	ENST00000509943.2	n.59+1472C>G		intron_variant	Intron 1 of 6	3
TILAM	ENST00000832079.1	n.155+160C>G		intron_variant	Intron 1 of 6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type I Pathogenic:1

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the c.103+5G nucleotide in the COL1A1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 836318). This variant has been observed in individual(s) with clinical features of osteogenesis imperfecta (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 1 of the COL1A1 gene. It does not directly change the encoded amino acid sequence of the COL1A1 protein. It affects a nucleotide within the consensus splice site of the intron. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Benign	0.96
PhyloP100		6.6
PromoterAI		-0.55	Under-expression

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.74		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555575835; hg19: chr17-48278767;