14-20429575-C-T

Position:

• chr14-20429575-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001365790.2(KLHL33):​c.1768G>A​(p.Ala590Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL33 NM_001365790.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39

Genes affected

KLHL33 (HGNC:31952): (kelch like family member 33)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL33	NM_001365790.2	c.1768G>A	p.Ala590Thr	missense_variant	4/5	ENST00000636854.3	NP_001352719.1
KLHL33	NM_001109997.3	c.976G>A	p.Ala326Thr	missense_variant	3/4		NP_001103467.2
KLHL33	XM_011536450.3	c.1768G>A	p.Ala590Thr	missense_variant	4/5		XP_011534752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL33	ENST00000636854.3	c.1768G>A	p.Ala590Thr	missense_variant	4/5	5	NM_001365790.2	ENSP00000490040.1
KLHL33	ENST00000637228.1	c.1768G>A	p.Ala590Thr	missense_variant	3/4	5		ENSP00000489731.1
KLHL33	ENST00000344581.4	c.976G>A	p.Ala326Thr	missense_variant	3/4	5		ENSP00000341549.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

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

Jul 22, 2024

The c.976G>A (p.A326T) alteration is located in exon 3 (coding exon 2) of the KLHL33 gene. This alteration results from a G to A substitution at nucleotide position 976, causing the alanine (A) at amino acid position 326 to be replaced by a threonine (T). 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	0.24
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;.;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.2	.;.;M
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.8	.;.;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0030	.;.;D
Sift4G	Uncertain	0.022	.;.;D
Polyphen		0.98	.;.;D
Vest4		0.66
MutPred		0.67		.;.;Gain of methylation at R330 (P = 0.1657);
MVP		0.35
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.72
gMVP		0.65

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: chr14-20897734;