13-45194182-C-T

Variant names:

• chr13-45194182-C-T
• NM_198404.3:c.386G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198404.3(KCTD4):​c.386G>A​(p.Arg129Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCTD4 NM_198404.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.37

Genes affected

KCTD4 (HGNC:23227): (potassium channel tetramerization domain containing 4) Predicted to be involved in protein homooligomerization. [provided by Alliance of Genome Resources, Apr 2022]

GTF2F2 (HGNC:4653): (general transcription factor IIF subunit 2) Predicted to enable RNA polymerase II general transcription initiation factor activity. Involved in transcription by RNA polymerase II. Located in microtubule cytoskeleton and nucleoplasm. Part of transcription preinitiation complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12959814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD4	NM_198404.3	c.386G>A	p.Arg129Lys	missense_variant	Exon 2 of 2	ENST00000379108.2	NP_940686.2
GTF2F2	NM_004128.3	c.305-13242C>T		intron_variant	Intron 4 of 7	ENST00000340473.8	NP_004119.1
GTF2F2	XM_011535052.4	c.382+10704C>T		intron_variant	Intron 5 of 8		XP_011533354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCTD4	ENST00000379108.2	c.386G>A	p.Arg129Lys	missense_variant	Exon 2 of 2	6	NM_198404.3	ENSP00000368402.1
GTF2F2	ENST00000340473.8	c.305-13242C>T		intron_variant	Intron 4 of 7	1	NM_004128.3	ENSP00000340823.6
GTF2F2	ENST00000706694.1	n.134-13242C>T		intron_variant	Intron 1 of 5			ENSP00000516507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.386G>A (p.R129K) alteration is located in exon 2 (coding exon 1) of the KCTD4 gene. This alteration results from a G to A substitution at nucleotide position 386, causing the arginine (R) at amino acid position 129 to be replaced by a lysine (K). 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	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.024
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.11
Sift	Benign	0.43	T
Sift4G	Benign	0.80	T
Polyphen		0.030	B
Vest4		0.10
MutPred		0.45		Gain of ubiquitination at R129 (P = 0.0211);
MVP		0.57
ClinPred		0.42	T
GERP RS		6.0
Varity_R		0.21
gMVP		0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-45768317;