chr1-52033196-G-C

Position:

• chr1-52033196-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138417.3(KTI12):​c.566C>G​(p.Thr189Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000521 in 1,614,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (0 hom.)
• Consequence: KTI12 NM_138417.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.222

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KTI12	NM_138417.3	c.566C>G	p.Thr189Ser	missense_variant	1/1	ENST00000371614.2	NP_612426.1
TXNDC12	NM_015913.4	c.159-4566C>G		intron_variant		ENST00000371626.9	NP_056997.1
TXNDC12	NR_046405.1	n.2089C>G		non_coding_transcript_exon_variant	3/3
TXNDC12	NR_046406.1	n.1966C>G		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KTI12	ENST00000371614.2	c.566C>G	p.Thr189Ser	missense_variant	1/1	6	NM_138417.3	ENSP00000360676.1
TXNDC12	ENST00000371626.9	c.159-4566C>G		intron_variant		1	NM_015913.4	ENSP00000360688.4
ENSG00000285839	ENST00000648686.1	n.155C>G		non_coding_transcript_exon_variant	1/7			ENSP00000498140.1
TXNDC12	ENST00000472624.5	n.159-2648C>G		intron_variant		5		ENSP00000477120.1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000294 AC: 74 AN: 251284 Hom.: 0 AF XY: 0.000294 AC XY: 40 AN XY: 135884

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000590

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000543 AC: 794 AN: 1461856 Hom.: 0 Cov.: 33 AF XY: 0.000538 AC XY: 391 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000655

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.000308 AC: 47 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74508

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000517 Hom.: 0

Bravo AF: 0.000230

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000264 AC: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000356

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

Apr 18, 2023

The c.566C>G (p.T189S) alteration is located in exon 1 (coding exon 1) of the KTI12 gene. This alteration results from a C to G substitution at nucleotide position 566, causing the threonine (T) at amino acid position 189 to be replaced by a serine (S). 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	0.088
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.3
DANN	Benign	0.57
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.030
Sift	Benign	0.58	T
Sift4G	Benign	0.98	T
Polyphen		0.0030	B
Vest4		0.056
MutPred		0.32		Gain of sheet (P = 0.0344);
MVP		0.26
MPC		0.50
ClinPred		0.039	T
GERP RS		-4.5
Varity_R		0.033
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138486051; hg19: chr1-52498868;