rs757879229
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000353.3(TAT):c.1250G>A(p.Arg417Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
TAT
NM_000353.3 missense
NM_000353.3 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 7.69
Genes affected
TAT (HGNC:11573): (tyrosine aminotransferase) This nuclear gene encodes a mitochondrial protein tyrosine aminotransferase which is present in the liver and catalyzes the conversion of L-tyrosine into p-hydroxyphenylpyruvate. Mutations in this gene cause tyrosinemia (type II, Richner-Hanhart syndrome), a disorder accompanied by major skin and corneal lesions, with possible cognitive disability. A regulator gene for tyrosine aminotransferase is X-linked. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
?
Variant 16-71568259-C-T is Pathogenic according to our data. Variant chr16-71568259-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 550062.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TAT | NM_000353.3 | c.1250G>A | p.Arg417Gln | missense_variant | 12/12 | ENST00000355962.5 | |
TAT-AS1 | NR_103852.1 | n.258+2058C>T | intron_variant, non_coding_transcript_variant | ||||
TAT-AS1 | NR_103851.1 | n.284+2058C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TAT | ENST00000355962.5 | c.1250G>A | p.Arg417Gln | missense_variant | 12/12 | 1 | NM_000353.3 | P1 | |
TAT-AS1 | ENST00000561529.1 | n.284+2058C>T | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251370Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135894
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461866Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727236
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Tyrosinemia type II Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2022 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TAT protein function. ClinVar contains an entry for this variant (Variation ID: 550062). This missense change has been observed in individual(s) with tyrosinemia (PMID: 21145993, 28255985; Invitae). This variant is present in population databases (rs757879229, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 417 of the TAT protein (p.Arg417Gln). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 04, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of stability (P = 0.187);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at