14-20429876-G-A

Variant summary

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

The NM_001365790.2(KLHL33):c.1592C>T(p.Ala531Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,399,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KLHL33 NM_001365790.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.29

Genes affected

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

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=0.16673419).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL33	NM_001365790.2	c.1592C>T	p.Ala531Val	missense_variant	3/5	ENST00000636854.3
KLHL33	NM_001109997.3	c.800C>T	p.Ala267Val	missense_variant	2/4
KLHL33	XM_011536450.3	c.1592C>T	p.Ala531Val	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL33	ENST00000636854.3	c.1592C>T	p.Ala531Val	missense_variant	3/5	5	NM_001365790.2	P1
KLHL33	ENST00000637228.1	c.1592C>T	p.Ala531Val	missense_variant	2/4	5
KLHL33	ENST00000344581.4	c.800C>T	p.Ala267Val	missense_variant	2/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1399626 Hom.: 0 Cov.: 34 AF XY: 0.00000145 AC XY: 1 AN XY: 690292

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: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Aug 30, 2022

The c.800C>T (p.A267V) alteration is located in exon 2 (coding exon 1) of the KLHL33 gene. This alteration results from a C to T substitution at nucleotide position 800, causing the alanine (A) at amino acid position 267 to be replaced by a valine (V). 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	0.079
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0033	T;.;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	0.80	D
PrimateAI	Benign	0.41	T
Polyphen		0.034	.;.;B
Vest4		0.15
MutPred		0.61		.;.;Loss of disorder (P = 0.0523);
MVP		0.092
ClinPred		0.27	T
GERP RS		2.9
Varity_R		0.074
gMVP		0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-20898035;