10-13233314-TGGGGCCTCCTAACCCTGACAAAGTATTCAATCCAATATACGACCTACAGTCAGGAAATAGGGTGTAATTTCTCATTCAGAGCTGCAGTCCCTTTGATACCCTGGGGTGAGCCCTTCGTGCCCAGCTGCATCCTGCTGCCCGGCTGACTGTGGGAGAGGAGGAGCCGGGGGGTGTGAGCAGAGGTGGTGATGGACGCGGGATGGGGTCCCTCCAGCATCCTTACCATTGACCTCATCTCTGGACTTGGGGGACCGCTTGCCGCGCCTCTTGAGGAAATTCGAGGCATCTGATTCCTGCATGAAAATCTTCTGTTTTGCATCTGAAACCCGGGAGAGGCCTGTCACCAGCAGTGTGGGGGTGCTGGGGCTGCTGCTTCGCTGGCTGCACCTGCCCTGCCCCGTGGGTGGCCCCTGCACTCACCTTCACTCGCCTCTTCTCCCGCCATCTGCATGGTGCCCACAGATACACTGGTTCCCTCTCTCAGCACTGCAGGACAAGGGCACAGAGTGAGGCTGCAGCATCAGAGGGGAGCCCAGACCCTGAGCTGAGTCCCCATCTCTCTTTCCAGGCTAAGCGTCCTGCCAGGGCCTGGCAGGGGGCCCGTGGTTTCTCACGTACCAGCTGCAGAGCCAATCTCCCCAGGAACCCACCAAGCAAGCTGGCTTGGGTTTTTTTTCTATTTTGTTTCTTTCTTTACTGTTTTTTATTATTATTATTATTTTTCTGTATTGCATTGTGTCCTACATGCACACGACACACACATACACACATGTTAACAATAAGCATACTCCTTTCTACCTGCATCACCTGAGCAGCCTTACCTGTGCATGGTAAGTCTCCCTTACCATGTAACTAACACCCTCCACCTTGACCCTCCTGTACTCACTAGACAGGAGCACCACGGCGGAGAAGCAAGACAGCAGGACGG-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_145314.3(UCMA):c.17_220+223del variant causes a splice acceptor, splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UCMA NM_145314.3 splice_acceptor, splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.915

Genes affected

UCMA (HGNC:25205): (upper zone of growth plate and cartilage matrix associated) This gene encodes a chondrocyte-specific, highly charged protein that is abundantly expressed in the upper immature zone of fetal and juvenile epiphyseal cartilage. The encoded protein undergoes proteolytic processing to generate a mature protein that is secreted into the extracellular matrix. The glutamic acid residues in the encoded protein undergo gamma carboxylation in a vitamin K-dependent manner. Undercarboxylation of the encoded protein is associated with osteoarthritis in humans. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.22781774 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UCMA	NM_145314.3	c.17_220+223del		splice_acceptor_variant, splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	1/5	ENST00000378681.8
UCMA	NM_001303118.2	c.17_124+420del		splice_acceptor_variant, splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	1/4
UCMA	NM_001303119.2	c.17_58+886del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UCMA	ENST00000378681.8	c.17_220+223del		splice_acceptor_variant, splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	1/5	1	NM_145314.3	P1
UCMA	ENST00000463405.2	c.17_154+223del		splice_acceptor_variant, splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	1/4	5

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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autism Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Apr 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-13275314;