rs1553648931

Positions:

• chr2-240874541-GCCTGGCAACTGGAGGTGCCGTTCCCCAGAACAGAGAGGACTTCGGGGAGAAGTCAGGAATTCGGTGTTGGACGTGGGAGGTCTGAGATGCCAGCTGGACCACACGGGAGGGTGAAGGAAGCGGCTGGGTGTGAGTCAGGAGCCTGGGGAGAGGCCGGGGCTGGCCCCTCCATCTGGAGTTGTAGAGACGGACACATTTAAAGTTTCAAGCCTGGCCAGTGTCCCCTGGGGCCCGAAAGCAGTCACCTTTGGGTGATGTGAGAAATGAAGGCTGACCCTGTAGGAGGGGCTGGGGGAGAGAAAGGGGCACACAGAGTGGAGGGAGCTGGCCTTGGTGCCCCCATGGCAGGGTCACACAGCTGGGCCCAAGGGCCAGCGGGACTGGACAGCTGAGGGACCCACGACCCACCCGGTCCCACTCTGGCCCCTGAGCACAAATGCAGCTGGGGCGGGCCCTCCTGGGGGCCCCACCCCGTCTCACTCCCGTGAAACAGGACAGCCAGCGAGACTGCCCTGGCCTTCAGCCCAAACTGAGAGGCTGGTGCTCAGCCTGCTTCTTTCTCCCCAGAAAGAAGATGTACTCCCGCAAGACGAAGCCCTTCTCCTTCTACCTGGACATCAAGTGGCTGGCCAACTTCTGGGGCTGTGACGACCAGCCCAGGATGTGAGGCCTGGCAGGGATGGGAAGGTGGAGGGCGCTGGGCATGGCTGAGAGGTGGGGCGCTGGCCTCTC-GTGAGA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000030.3(AGXT):​c.680+480_776+69delinsTGAGA 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: AGXT NM_000030.3 splice_acceptor, splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.997

Genes affected

AGXT (HGNC:341): (alanine--glyoxylate aminotransferase) This gene is expressed only in the liver and the encoded protein is localized mostly in the peroxisomes, where it is involved in glyoxylate detoxification. Mutations in this gene, some of which alter subcellular targetting, have been associated with type I primary hyperoxaluria. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-240874542-CCTGGCAACTGGAGGTGCCGTTCCCCAGAACAGAGAGGACTTCGGGGAGAAGTCAGGAATTCGGTGTTGGACGTGGGAGGTCTGAGATGCCAGCTGGACCACACGGGAGGGTGAAGGAAGCGGCTGGGTGTGAGTCAGGAGCCTGGGGAGAGGCCGGGGCTGGCCCCTCCATCTGGAGTTGTAGAGACGGACACATTTAAAGTTTCAAGCCTGGCCAGTGTCCCCTGGGGCCCGAAAGCAGTCACCTTTGGGTGATGTGAGAAATGAAGGCTGACCCTGTAGGAGGGGCTGGGGGAGAGAAAGGGGCACACAGAGTGGAGGGAGCTGGCCTTGGTGCCCCCATGGCAGGGTCACACAGCTGGGCCCAAGGGCCAGCGGGACTGGACAGCTGAGGGACCCACGACCCACCCGGTCCCACTCTGGCCCCTGAGCACAAATGCAGCTGGGGCGGGCCCTCCTGGGGGCCCCACCCCGTCTCACTCCCGTGAAACAGGACAGCCAGCGAGACTGCCCTGGCCTTCAGCCCAAACTGAGAGGCTGGTGCTCAGCCTGCTTCTTTCTCCCCAGAAAGAAGATGTACTCCCGCAAGACGAAGCCCTTCTCCTTCTACCTGGACATCAAGTGGCTGGCCAACTTCTGGGGCTGTGACGACCAGCCCAGGATGTGAGGCCTGGCAGGGATGGGAAGGTGGAGGGCGCTGGGCATGGCTGAGAGGTGGGGCGCTGGCCTCTC-TGAGA is Pathogenic according to our data. Variant chr2-240874542-CCTGGCAACTGGAGGTGCCGTTCCCCAGAACAGAGAGGACTTCGGGGAGAAGTCAGGAATTCGGTGTTGGACGTGGGAGGTCTGAGATGCCAGCTGGACCACACGGGAGGGTGAAGGAAGCGGCTGGGTGTGAGTCAGGAGCCTGGGGAGAGGCCGGGGCTGGCCCCTCCATCTGGAGTTGTAGAGACGGACACATTTAAAGTTTCAAGCCTGGCCAGTGTCCCCTGGGGCCCGAAAGCAGTCACCTTTGGGTGATGTGAGAAATGAAGGCTGACCCTGTAGGAGGGGCTGGGGGAGAGAAAGGGGCACACAGAGTGGAGGGAGCTGGCCTTGGTGCCCCCATGGCAGGGTCACACAGCTGGGCCCAAGGGCCAGCGGGACTGGACAGCTGAGGGACCCACGACCCACCCGGTCCCACTCTGGCCCCTGAGCACAAATGCAGCTGGGGCGGGCCCTCCTGGGGGCCCCACCCCGTCTCACTCCCGTGAAACAGGACAGCCAGCGAGACTGCCCTGGCCTTCAGCCCAAACTGAGAGGCTGGTGCTCAGCCTGCTTCTTTCTCCCCAGAAAGAAGATGTACTCCCGCAAGACGAAGCCCTTCTCCTTCTACCTGGACATCAAGTGGCTGGCCAACTTCTGGGGCTGTGACGACCAGCCCAGGATGTGAGGCCTGGCAGGGATGGGAAGGTGGAGGGCGCTGGGCATGGCTGAGAGGTGGGGCGCTGGCCTCTC-TGAGA is described in ClinVar as [Pathogenic]. Clinvar id is 204196.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGXT	NM_000030.3	c.680+480_776+69delinsTGAGA		splice_acceptor_variant, splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	7/11	ENST00000307503.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGXT	ENST00000307503.4	c.680+480_776+69delinsTGAGA		splice_acceptor_variant, splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	7/11	1	NM_000030.3	P1
AGXT	ENST00000476698.1	n.333-567_428+69delinsTGAGA		splice_acceptor_variant, splice_donor_variant, splice_donor_5th_base_variant, non_coding_transcript_exon_variant, intron_variant	3/4	5

Frequencies

GnomAD3 genomes Cov.: 34

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

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Primary hyperoxaluria, type I Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Thalassemia Center, San Luigi University Hospital	Oct 27, 2023	ACMG:PVS1 PM1 PM2 PM4 -
Pathogenic, no assertion criteria provided	research	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -

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: rs1553648931; hg19: chr2-241813959;