16-29925839-C-T

Position:

• chr16-29925839-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_178863.5(KCTD13):​c.195G>A​(p.Met65Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: KCTD13 NM_178863.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47

Genes affected

KCTD13 (HGNC:22234): (potassium channel tetramerization domain containing 13) Enables identical protein binding activity and small GTPase binding activity. Contributes to ubiquitin-protein transferase activity. Involved in several processes, including cellular protein metabolic process; negative regulation of Rho protein signal transduction; and stress fiber assembly. Located in nuclear body. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCTD13	NM_178863.5	c.195G>A	p.Met65Ile	missense_variant	1/6	ENST00000568000.6	NP_849194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCTD13	ENST00000568000.6	c.195G>A	p.Met65Ile	missense_variant	1/6	1	NM_178863.5	ENSP00000455785.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 Cov.: 33 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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

May 15, 2024

The c.195G>A (p.M65I) alteration is located in exon 1 (coding exon 1) of the KCTD13 gene. This alteration results from a G to A substitution at nucleotide position 195, causing the methionine (M) at amino acid position 65 to be replaced by an isoleucine (I). 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	0.96
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Uncertain	0.099	D
MutationAssessor	Pathogenic	3.0	M;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.5	D;.;.
Sift	Uncertain	0.0030	D;.;.
Sift4G	Uncertain	0.012	D;D;.
Polyphen		0.79	P;.;.
Vest4		0.49
MutPred		0.60		Loss of catalytic residue at M65 (P = 0.0213);Loss of catalytic residue at M65 (P = 0.0213);Loss of catalytic residue at M65 (P = 0.0213);
MVP		0.77
MPC		1.5
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.74
gMVP		0.69

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: rs748629827; hg19: chr16-29937160;