rs2783175

Positions:

• chr1-52033189-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138417.3(KTI12):​c.573T>A​(p.Asp191Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0492 in 1,614,150 control chromosomes in the GnomAD database, including 2,308 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.055 (285 hom., cov: 33)
  • Exomes 𝑓: 0.049 (2023 hom.)
• Consequence: KTI12 NM_138417.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.44

Genes affected

KTI12 (HGNC:25160): (KTI12 chromatin associated homolog) Predicted to enable ATP binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II and tRNA wobble uridine modification. [provided by Alliance of Genome Resources, Apr 2022]

TXNDC12 (HGNC:24626): (thioredoxin domain containing 12) This gene encodes a member of the thioredoxin superfamily. Members of this family are characterized by a conserved active motif called the thioredoxin fold that catalyzes disulfide bond formation and isomerization. This protein localizes to the endoplasmic reticulum and has a single atypical active motif. The encoded protein is mainly involved in catalyzing native disulfide bond formation and displays activity similar to protein-disulfide isomerases. This protein may play a role in defense against endoplasmic reticulum stress. Alternate splicing results in both coding and non-coding variants. [provided by RefSeq, Mar 2012]

ENSG00000285839 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013937652).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KTI12	NM_138417.3	c.573T>A	p.Asp191Glu	missense_variant	1/1	ENST00000371614.2	NP_612426.1
TXNDC12	NM_015913.4	c.159-4559T>A		intron_variant		ENST00000371626.9	NP_056997.1
TXNDC12	NR_046405.1	n.2096T>A		non_coding_transcript_exon_variant	3/3
TXNDC12	NR_046406.1	n.1973T>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KTI12	ENST00000371614.2	c.573T>A	p.Asp191Glu	missense_variant	1/1	6	NM_138417.3	ENSP00000360676.1
TXNDC12	ENST00000371626.9	c.159-4559T>A		intron_variant		1	NM_015913.4	ENSP00000360688.4
ENSG00000285839	ENST00000648686.1	n.162T>A		non_coding_transcript_exon_variant	1/7			ENSP00000498140.1
TXNDC12	ENST00000472624.5	n.159-2641T>A		intron_variant		5		ENSP00000477120.1

Frequencies

GnomAD3 genomes AF: 0.0544 AC: 8280 AN: 152186 Hom.: 279 Cov.: 33

Gnomad AFR AF: 0.0735

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0605

Gnomad ASJ AF: 0.0283

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.0350

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0438

Gnomad OTH AF: 0.0578

GnomAD3 exomes AF: 0.0593 AC: 14895 AN: 251260 Hom.: 602 AF XY: 0.0556 AC XY: 7552 AN XY: 135860

Gnomad AFR exome AF: 0.0764

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.0280

Gnomad EAS exome AF: 0.142

Gnomad SAS exome AF: 0.0374

Gnomad FIN exome AF: 0.0229

Gnomad NFE exome AF: 0.0450

Gnomad OTH exome AF: 0.0510

GnomAD4 exome AF: 0.0486 AC: 71070 AN: 1461846 Hom.: 2023 Cov.: 33 AF XY: 0.0477 AC XY: 34672 AN XY: 727228

Gnomad4 AFR exome AF: 0.0739

Gnomad4 AMR exome AF: 0.100

Gnomad4 ASJ exome AF: 0.0293

Gnomad4 EAS exome AF: 0.112

Gnomad4 SAS exome AF: 0.0351

Gnomad4 FIN exome AF: 0.0215

Gnomad4 NFE exome AF: 0.0461

Gnomad4 OTH exome AF: 0.0533

GnomAD4 genome AF: 0.0546 AC: 8317 AN: 152304 Hom.: 285 Cov.: 33 AF XY: 0.0525 AC XY: 3910 AN XY: 74476

Gnomad4 AFR AF: 0.0740

Gnomad4 AMR AF: 0.0610

Gnomad4 ASJ AF: 0.0283

Gnomad4 EAS AF: 0.130

Gnomad4 SAS AF: 0.0352

Gnomad4 FIN AF: 0.0191

Gnomad4 NFE AF: 0.0438

Gnomad4 OTH AF: 0.0596

Alfa AF: 0.0497 Hom.: 174

Bravo AF: 0.0617

TwinsUK AF: 0.0480 AC: 178

ALSPAC AF: 0.0514 AC: 198

ESP6500AA AF: 0.0724 AC: 319

ESP6500EA AF: 0.0463 AC: 398

ExAC AF: 0.0595 AC: 7223

Asia WGS AF: 0.0910 AC: 315 AN: 3478

EpiCase AF: 0.0441

EpiControl AF: 0.0466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0060
DANN	Benign	0.56
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.77	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.046
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.012
MutPred		0.098		Loss of helix (P = 0.079);
MPC		0.52
ClinPred		0.0018	T
GERP RS		-5.7
Varity_R		0.040
gMVP		0.085

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: rs2783175; hg19: chr1-52498861; COSMIC: COSV65405640; COSMIC: COSV65405640;