12-120446488-C-T

Variant names:

• chr12-120446488-C-T
• rs17431446
• NM_176818.3:c.8C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_176818.3(GATC):​c.8C>T​(p.Ser3Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0566 in 1,606,746 control chromosomes in the GnomAD database, including 3,074 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (261 hom., cov: 33)
  • Exomes 𝑓: 0.058 (2813 hom.)
• Consequence: GATC NM_176818.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.479
• Publications: 14 publications found

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:):

TRIAP1 (HGNC:26937): (TP53 regulated inhibitor of apoptosis 1) Enables p53 binding activity. Contributes to phosphatidic acid transfer activity. Involved in several processes, including DNA damage response, signal transduction by p53 class mediator; negative regulation of apoptotic process; and positive regulation of phospholipid transport. Located in mitochondrial intermembrane space and nucleoplasm. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017315149).
• BP6: Variant 12-120446488-C-T is Benign according to our data. Variant chr12-120446488-C-T is described in ClinVar as Benign. ClinVar VariationId is 1294746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0922 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176818.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATC	NM_176818.3	MANE Select	c.8C>T	p.Ser3Leu	missense	Exon 1 of 4	NP_789788.1	O43716
	GATC	NR_033684.2		n.45C>T		non_coding_transcript_exon	Exon 1 of 5
	TRIAP1	NM_016399.3	MANE Select	c.-116G>A		upstream_gene	N/A	NP_057483.1	O43715

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATC	ENST00000551765.6	TSL:1 MANE Select	c.8C>T	p.Ser3Leu	missense	Exon 1 of 4	ENSP00000446872.1	O43716
	ENSG00000111780	ENST00000551806.1	TSL:3	c.175-169C>T		intron	N/A	ENSP00000450281.1	H0YIV9
	GATC	ENST00000920762.1		c.8C>T	p.Ser3Leu	missense	Exon 1 of 4	ENSP00000590821.1

Frequencies

GnomAD3 genomes AF: 0.0454 AC: 6916 AN: 152226 Hom.: 263 Cov.: 33

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0387

Gnomad ASJ AF: 0.0573

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.0944

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0595

Gnomad OTH AF: 0.0449

GnomAD2 exomes AF: 0.0564 AC: 13974 AN: 247570 AF XY: 0.0610

Gnomad AFR exome AF: 0.00679

Gnomad AMR exome AF: 0.0281

Gnomad ASJ exome AF: 0.0561

Gnomad EAS exome AF: 0.00301

Gnomad FIN exome AF: 0.0983

Gnomad NFE exome AF: 0.0609

Gnomad OTH exome AF: 0.0545

GnomAD4 exome AF: 0.0577 AC: 83976 AN: 1454402 Hom.: 2813 Cov.: 31 AF XY: 0.0598 AC XY: 43198 AN XY: 722538

African (AFR) AF: 0.00840 AC: 280 AN: 33324

American (AMR) AF: 0.0291 AC: 1285 AN: 44196

Ashkenazi Jewish (ASJ) AF: 0.0528 AC: 1367 AN: 25890

East Asian (EAS) AF: 0.00185 AC: 73 AN: 39532

South Asian (SAS) AF: 0.104 AC: 8900 AN: 85788

European-Finnish (FIN) AF: 0.0931 AC: 4884 AN: 52454

Middle Eastern (MID) AF: 0.0618 AC: 355 AN: 5746

European-Non Finnish (NFE) AF: 0.0574 AC: 63546 AN: 1107486

Other (OTH) AF: 0.0548 AC: 3286 AN: 59986

GnomAD4 genome AF: 0.0453 AC: 6908 AN: 152344 Hom.: 261 Cov.: 33 AF XY: 0.0473 AC XY: 3525 AN XY: 74494

African (AFR) AF: 0.0102 AC: 426 AN: 41590

American (AMR) AF: 0.0386 AC: 591 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0573 AC: 199 AN: 3472

East Asian (EAS) AF: 0.00347 AC: 18 AN: 5186

South Asian (SAS) AF: 0.0996 AC: 481 AN: 4830

European-Finnish (FIN) AF: 0.0944 AC: 1001 AN: 10608

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0595 AC: 4047 AN: 68030

Other (OTH) AF: 0.0440 AC: 93 AN: 2114

Alfa AF: 0.0510 Hom.: 431

Bravo AF: 0.0373

TwinsUK AF: 0.0585 AC: 217

ALSPAC AF: 0.0618 AC: 238

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.0571 AC: 491

ExAC AF: 0.0556 AC: 6751

Asia WGS AF: 0.0400 AC: 139 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.48
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.076
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.061	T
Polyphen		0.0	B
Vest4		0.20
MPC		0.46
ClinPred		0.067	T
GERP RS		2.2
PromoterAI		0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.36
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17431446; hg19: chr12-120884291; COSMIC: COSV56663466; COSMIC: COSV56663466;