13-45194056-C-T

Variant summary

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

The NM_198404.3(KCTD4):​c.512G>A​(p.Arg171His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R171C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

KCTD4
NM_198404.3 missense

Scores

5
8
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank MANE Protein UniProt
KCTD4NM_198404.3 linkc.512G>A p.Arg171His missense_variant Exon 2 of 2 ENST00000379108.2 NP_940686.2 Q8WVF5
GTF2F2NM_004128.3 linkc.305-13368C>T intron_variant Intron 4 of 7 ENST00000340473.8 NP_004119.1 P13984A0A024RDU9
GTF2F2XM_011535052.4 linkc.382+10578C>T intron_variant Intron 5 of 8 XP_011533354.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCTD4ENST00000379108.2 linkc.512G>A p.Arg171His missense_variant Exon 2 of 2 6 NM_198404.3 ENSP00000368402.1 Q8WVF5
GTF2F2ENST00000340473.8 linkc.305-13368C>T intron_variant Intron 4 of 7 1 NM_004128.3 ENSP00000340823.6 P13984
GTF2F2ENST00000706694.1 linkn.134-13368C>T intron_variant Intron 1 of 5 ENSP00000516507.1 A0A9L9PX76

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
250848
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135542
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000150
AC:
22
AN:
1461808
Hom.:
0
Cov.:
32
AF XY:
0.00000963
AC XY:
7
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000312
Hom.:
0
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 20, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.512G>A (p.R171H) 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 512, causing the arginine (R) at amino acid position 171 to be replaced by a histidine (H). 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
Pathogenic
0.64
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.055
T
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.90
D
M_CAP
Benign
0.020
T
MetaRNN
Uncertain
0.66
D
MetaSVM
Benign
-0.64
T
MutationAssessor
Benign
0.0
N
PrimateAI
Uncertain
0.79
T
PROVEAN
Benign
-0.91
N
REVEL
Uncertain
0.34
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0050
D
Polyphen
1.0
D
Vest4
0.56
MutPred
0.55
Gain of catalytic residue at K169 (P = 0);
MVP
0.92
ClinPred
0.94
D
GERP RS
5.9
Varity_R
0.48
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1361007987; hg19: chr13-45768191; COSMIC: COSV100477595; API