13-45194090-T-C

Variant names:

• chr13-45194090-T-C
• rs1872767842
• NM_198404.3:c.478A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_198404.3(KCTD4):​c.478A>G​(p.Asn160Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCTD4 NM_198404.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30809844).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD4	NM_198404.3	c.478A>G	p.Asn160Asp	missense_variant	Exon 2 of 2	ENST00000379108.2	NP_940686.2
GTF2F2	NM_004128.3	c.305-13334T>C		intron_variant	Intron 4 of 7	ENST00000340473.8	NP_004119.1
GTF2F2	XM_011535052.4	c.382+10612T>C		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.478A>G	p.Asn160Asp	missense_variant	Exon 2 of 2	6	NM_198404.3	ENSP00000368402.1
GTF2F2	ENST00000340473.8	c.305-13334T>C		intron_variant	Intron 4 of 7	1	NM_004128.3	ENSP00000340823.6
GTF2F2	ENST00000706694.1	n.134-13334T>C		intron_variant	Intron 1 of 5			ENSP00000516507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461820 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727216

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.478A>G (p.N160D) alteration is located in exon 2 (coding exon 1) of the KCTD4 gene. This alteration results from a A to G substitution at nucleotide position 478, causing the asparagine (N) at amino acid position 160 to be replaced by an aspartic acid (D). 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	Uncertain	0.43
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.11
Sift	Benign	0.037	D
Sift4G	Benign	0.14	T
Polyphen		0.37	B
Vest4		0.38
MutPred		0.45		Gain of catalytic residue at A161 (P = 0.0043);
MVP		0.79
ClinPred		0.81	D
GERP RS		5.9
Varity_R		0.20
gMVP		0.70

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: rs1872767842; hg19: chr13-45768225;