14-20429261-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.1982C>T(p.Pro661Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000197 in 152,146 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: 𝑓 0.000020 (0 hom., cov: 32)
• Consequence: KLHL33 NM_001365790.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.14

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=0.11403856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL33	NM_001365790.2	c.1982C>T	p.Pro661Leu	missense_variant	5/5	ENST00000636854.3
KLHL33	NM_001109997.3	c.1190C>T	p.Pro397Leu	missense_variant	4/4
KLHL33	XM_011536450.3	c.1982C>T	p.Pro661Leu	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL33	ENST00000636854.3	c.1982C>T	p.Pro661Leu	missense_variant	5/5	5	NM_001365790.2	P1
KLHL33	ENST00000344581.4	c.1190C>T	p.Pro397Leu	missense_variant	4/4	5
KLHL33	ENST00000637228.1	c.*141C>T		3_prime_UTR_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74314

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

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 02, 2021

The c.1190C>T (p.P397L) alteration is located in exon 4 (coding exon 3) of the KLHL33 gene. This alteration results from a C to T substitution at nucleotide position 1190, causing the proline (P) at amino acid position 397 to be replaced by a leucine (L). 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	0.11
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	23
Dann	Benign	0.95
DEOGEN2	Benign	0.010	T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.050
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.96	D
PrimateAI	Benign	0.37	T
Polyphen		0.20	.;B
Vest4		0.34
MVP		0.34
ClinPred		0.33	T
GERP RS		5.4
Varity_R		0.089
gMVP		0.40

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: rs1354607124; hg19: chr14-20897420;