rs376766195

chr4-151719458-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_004564.3(GATB):c.408T>G(p.Phe136Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,459,878 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: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: GATB NM_004564.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.98

Genes affected

GATB (HGNC:8849): (glutamyl-tRNA amidotransferase subunit B) Enables glutaminyl-tRNA synthase (glutamine-hydrolyzing) activity. Involved in glutaminyl-tRNAGln biosynthesis via transamidation and mitochondrial translation. Located in mitochondrion. Part of glutamyl-tRNA(Gln) amidotransferase complex. Implicated in combined oxidative phosphorylation deficiency 41. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 4-151719458-A-C is Pathogenic according to our data. Variant chr4-151719458-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 559412.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATB	NM_004564.3	c.408T>G	p.Phe136Leu	missense_variant	3/13	ENST00000263985.11
GATB	NM_001363341.2	c.408T>G	p.Phe136Leu	missense_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATB	ENST00000263985.11	c.408T>G	p.Phe136Leu	missense_variant	3/13	1	NM_004564.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249300 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134842

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1459878 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 726216

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation deficiency 41 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 10, 2020

- -

Cardiomyopathy, mitochondrial Pathogenic:1

Pathogenic, criteria provided, single submitter

research

The Genetics Institute, Rambam Health Care Campus

May 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.086	D
MutationAssessor	Pathogenic	3.4	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.025	D;D;D
Sift4G	Uncertain	0.039	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.90
MutPred		0.91		Loss of methylation at K133 (P = 0.0798);Loss of methylation at K133 (P = 0.0798);Loss of methylation at K133 (P = 0.0798);
MVP		0.88
MPC		0.65
ClinPred		0.98	D
GERP RS		3.1
Varity_R		0.90
gMVP		0.74

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: rs376766195; hg19: chr4-152640610;