NM_001392073.1:c.-411C>T

Variant names:

• chr20-18142250-C-T
• rs76168870
• NM_001392073.1:c.-411C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001392073.1(KAT14):​c.-411C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000146 in 1,536,864 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: KAT14 NM_001392073.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51

Genes affected

KAT14 (HGNC:15904): (lysine acetyltransferase 14) CSRP2 is a protein containing two LIM domains, which are double zinc finger motifs found in proteins of diverse function. CSRP2 and some related proteins are thought to act as protein adapters, bridging two or more proteins to form a larger protein complex. The protein encoded by this gene binds to one of the LIM domains of CSRP2 and contains an acetyltransferase domain. Although the encoded protein has been detected in the cytoplasm, it is predominantly a nuclear protein. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jun 2011]

PET117 (HGNC:40045): (PET117 cytochrome c oxidase chaperone) Predicted to be involved in mitochondrial cytochrome c oxidase assembly. Located in mitochondrion. Implicated in cytochrome-c oxidase deficiency disease. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.012208074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAT14	NM_001392073.1	c.-411C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 11	ENST00000688188.1	NP_001379002.1
PET117	NM_001164811.2	c.139C>T	p.Arg47Trp	missense_variant	Exon 2 of 2	ENST00000432901.4	NP_001158283.1
KAT14	NM_001392073.1	c.-411C>T		5_prime_UTR_variant	Exon 2 of 11	ENST00000688188.1	NP_001379002.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KAT14	ENST00000688188	c.-411C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 11		NM_001392073.1	ENSP00000508684.1
PET117	ENST00000432901.4	c.139C>T	p.Arg47Trp	missense_variant	Exon 2 of 2	1	NM_001164811.2	ENSP00000397881.2
KAT14	ENST00000688188	c.-411C>T		5_prime_UTR_variant	Exon 2 of 11		NM_001392073.1	ENSP00000508684.1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 151936 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000804 AC: 114 AN: 141848 Hom.: 1 AF XY: 0.000593 AC XY: 45 AN XY: 75862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00415

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000471

Gnomad SAS exome AF: 0.0000440

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000514

Gnomad OTH exome AF: 0.000711

GnomAD4 exome AF: 0.000138 AC: 191 AN: 1384810 Hom.: 1 Cov.: 30 AF XY: 0.000119 AC XY: 81 AN XY: 683306

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00390

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000392

Gnomad4 SAS exome AF: 0.0000253

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000232

Gnomad4 OTH exome AF: 0.000173

GnomAD4 genome AF: 0.000224 AC: 34 AN: 152054 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74330

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000104 Hom.: 1

Bravo AF: 0.000397

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000958 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.139C>T (p.R47W) alteration is located in exon 2 (coding exon 2) of the PET117 gene. This alteration results from a C to T substitution at nucleotide position 139, causing the arginine (R) at amino acid position 47 to be replaced by a tryptophan (W). 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	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	-0.036	T
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Vest4		0.17
MVP		0.28
ClinPred		0.14	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.46
gMVP		0.23

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: rs76168870; hg19: chr20-18122894; COSMIC: COSV100890039; COSMIC: COSV100890039;