rs118203914

Positions:

• chr16-71576247-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000353.3(TAT):​c.169C>T​(p.Arg57Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,461,806 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: TAT NM_000353.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.88

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]

TAT-AS1 (HGNC:51369): (TAT antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-71576247-G-A is Pathogenic according to our data. Variant chr16-71576247-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAT	NM_000353.3	c.169C>T	p.Arg57Ter	stop_gained	2/12	ENST00000355962.5	NP_000344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAT	ENST00000355962.5	c.169C>T	p.Arg57Ter	stop_gained	2/12	1	NM_000353.3	ENSP00000348234	P1
TAT	ENST00000566010.1	n.265C>T		non_coding_transcript_exon_variant	2/2	1
TAT-AS1	ENST00000561529.1	n.751-1818G>A		intron_variant, non_coding_transcript_variant		5
TAT	ENST00000566094.5	n.265C>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251140 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135772

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461806 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinemia type II Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 30, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 18, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 402). This premature translational stop signal has been observed in individuals with tyrosinemia (PMID: 1357662, 9544843). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs118203914, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg57*) in the TAT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TAT are known to be pathogenic (PMID: 9544843). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1992	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 26, 2018

The R57X variant in the TAT gene has been reported previously in association with autosomal recessive tyrosinemia type II, when present in the homozygous state or when in trans with another disease-causing variant (Natt et al., 1992; Huhn et al., 1998). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R57X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret R57X as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A
Vest4		0.91
GERP RS		5.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs118203914; hg19: chr16-71610150; COSMIC: COSV63532532;