rs118203916

chr16-71568260-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000353.3(TAT):c.1249C>T(p.Arg417Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,010 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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: TAT NM_000353.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.88

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-71568260-G-A is Pathogenic according to our data. Variant chr16-71568260-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAT	NM_000353.3	c.1249C>T	p.Arg417Ter	stop_gained	12/12	ENST00000355962.5
TAT-AS1	NR_103852.1	n.258+2059G>A		intron_variant, non_coding_transcript_variant
TAT-AS1	NR_103851.1	n.284+2059G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAT	ENST00000355962.5	c.1249C>T	p.Arg417Ter	stop_gained	12/12	1	NM_000353.3	P1
TAT-AS1	ENST00000561529.1	n.284+2059G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74316

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinemia type II Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 12, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects TAT function (PMID: 1357662). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 404). This premature translational stop signal has been observed in individuals with tyrosinemia type II (PMID: 1357662, 16917729). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs118203916, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg417*) in the TAT gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 38 amino acid(s) of the TAT protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 03, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 15, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	38
Dann	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A
Vest4		0.79
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs118203916; hg19: chr16-71602163; COSMIC: COSV63533110; COSMIC: COSV63533110;