chr2-240877550-G-C

Variant names:

• chr2-240877550-G-C
• NM_000030.3:c.860G>C
• AGXT p.Ser287Thr

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 9P and 1B. PS1 PM1 PM2 PP2 BP4

The NM_000030.3(AGXT):​c.860G>C​(p.Ser287Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S287G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.179
• Publications: 0 publications found

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]

AGXT Gene-Disease associations (from GenCC):

• alanine glyoxylate aminotransferase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• primary hyperoxaluria type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women's Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_000030.3 (AGXT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 8 uncertain in NM_000030.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 130 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: -0.26789 (below the threshold of 3.09). Trascript score misZ: -0.48778 (below the threshold of 3.09). GenCC associations: The gene is linked to primary hyperoxaluria type 1, alanine glyoxylate aminotransferase deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33924788).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000030.3. 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
	AGXT	NM_000030.3	MANE Select	c.860G>C	p.Ser287Thr	missense	Exon 9 of 11	NP_000021.1	P21549

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGXT	ENST00000307503.4	TSL:1 MANE Select	c.860G>C	p.Ser287Thr	missense	Exon 9 of 11	ENSP00000302620.3	P21549
	AGXT	ENST00000908235.1		c.1133G>C	p.Ser378Thr	missense	Exon 10 of 12	ENSP00000578294.1
	AGXT	ENST00000908236.1		c.1049G>C	p.Ser350Thr	missense	Exon 10 of 12	ENSP00000578295.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.10	N
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.18
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.56
Sift	Benign	0.32	T
Sift4G	Benign	0.45	T
Varity_R		0.44
gMVP		0.89
Mutation Taster		=82/18	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-241816967;