12-120457177-C-A

Position:

• chr12-120457177-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_176818.3(GATC):​c.356C>A​(p.Pro119Gln) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GATC NM_176818.3 missense, splice_region
• Scores: Splicing: ADA: 0.9255
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.32

Genes affected

GATC (HGNC:25068): (glutamyl-tRNA amidotransferase subunit C) 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 42. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000111780 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATC	NM_176818.3	c.356C>A	p.Pro119Gln	missense_variant, splice_region_variant	3/4	ENST00000551765.6	NP_789788.1
GATC	NR_033684.2	n.491C>A		splice_region_variant, non_coding_transcript_exon_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATC	ENST00000551765.6	c.356C>A	p.Pro119Gln	missense_variant, splice_region_variant	3/4	1	NM_176818.3	ENSP00000446872.1
ENSG00000111780	ENST00000551806.1	c.449C>A	p.Pro150Gln	missense_variant, splice_region_variant	4/5	3		ENSP00000450281.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1454608 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 724216

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2023

The c.356C>A (p.P119Q) alteration is located in exon 3 (coding exon 3) of the GATC gene. This alteration results from a C to A substitution at nucleotide position 356, causing the proline (P) at amino acid position 119 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-7.7	D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.97	D;.
Vest4		0.82
MutPred		0.64		Gain of solvent accessibility (P = 0.1045);.;
MVP		0.62
MPC		1.3
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.80
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Pathogenic	0.79
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: rs747037373; hg19: chr12-120894980;