NM_000088.4:c.805-36_810delCACAGGTTCTTACCTTCTACCTCTTTCCTGCTTTAGGGTTTC

Variant names:

• chr17-50196664-TGAAACCCTAAAGCAGGAAAGAGGTAGAAGGTAAGAACCTGTG-T
• rs1555574450
• NM_000088.4:c.805-36_810delCACAGGTTCTTACCTTCTACCTCTTTCCTGCTTTAGGGTTTC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000088.4(COL1A1):​c.805-36_810delCACAGGTTCTTACCTTCTACCTCTTTCCTGCTTTAGGGTTTC​(p.Gly269_Ser271del) variant causes a splice acceptor, conservative inframe deletion, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL1A1 NM_000088.4 splice_acceptor, conservative_inframe_deletion, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.10

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_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.012286689 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.4, offset of 8, new splice context is: aggctgttccaccccctcAGtgg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-50196664-TGAAACCCTAAAGCAGGAAAGAGGTAGAAGGTAAGAACCTGTG-T is Pathogenic according to our data. Variant chr17-50196664-TGAAACCCTAAAGCAGGAAAGAGGTAGAAGGTAAGAACCTGTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 447146.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.805-36_810delCACAGGTTCTTACCTTCTACCTCTTTCCTGCTTTAGGGTTTC	p.Gly269_Ser271del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 12 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.805-36_810delCACAGGTTCTTACCTTCTACCTCTTTCCTGCTTTAGGGTTTC	p.Gly269_Ser271del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 12 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.805-36_810delCACAGGTTCTTACCTTCTACCTCTTTCCTGCTTTAGGGTTTC	p.Gly269_Ser271del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 12 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.805-36_810delCACAGGTTCTTACCTTCTACCTCTTTCCTGCTTTAGGGTTTC	p.Gly269_Ser271del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 12 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.805-36_810delCACAGGTTCTTACCTTCTACCTCTTTCCTGCTTTAGGGTTTC	p.Gly269_Ser271del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 12 of 51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000495677.1	n.532-36_537delCACAGGTTCTTACCTTCTACCTCTTTCCTGCTTTAGGGTTTC		splice_acceptor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	Exon 7 of 8	3
COL1A1	ENST00000485870.1	n.-111_-70delCACAGGTTCTTACCTTCTACCTCTTTCCTGCTTTAGGGTTTC		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

May 23, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555574450; hg19: chr17-48274025;