14-20429825-C-T

Variant summary

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

The NM_001365790.2(KLHL33):c.1643G>A(p.Ser548Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000287 in 1,393,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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: 0.0000029 (0 hom.)
• Consequence: KLHL33 NM_001365790.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.39

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=0.2180328).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL33	NM_001365790.2	c.1643G>A	p.Ser548Asn	missense_variant	3/5	ENST00000636854.3
KLHL33	NM_001109997.3	c.851G>A	p.Ser284Asn	missense_variant	2/4
KLHL33	XM_011536450.3	c.1643G>A	p.Ser548Asn	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL33	ENST00000636854.3	c.1643G>A	p.Ser548Asn	missense_variant	3/5	5	NM_001365790.2	P1
KLHL33	ENST00000637228.1	c.1643G>A	p.Ser548Asn	missense_variant	2/4	5
KLHL33	ENST00000344581.4	c.851G>A	p.Ser284Asn	missense_variant	2/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000653 AC: 1 AN: 153042 Hom.: 0 AF XY: 0.0000124 AC XY: 1 AN XY: 80576

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000169

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1393870 Hom.: 0 Cov.: 34 AF XY: 0.00000291 AC XY: 2 AN XY: 686934

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: 0.00000372

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

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

Jun 11, 2021

The c.851G>A (p.S284N) alteration is located in exon 2 (coding exon 1) of the KLHL33 gene. This alteration results from a G to A substitution at nucleotide position 851, causing the serine (S) at amino acid position 284 to be replaced by an asparagine (N). 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	0.20
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0059	T;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	0.94	N
PrimateAI	Benign	0.47	T
Polyphen		0.96	.;.;P
Vest4		0.13
MutPred		0.37		.;.;Loss of phosphorylation at T288 (P = 0.1001);
MVP		0.17
ClinPred		0.69	D
GERP RS		4.7
Varity_R		0.15
gMVP		0.29

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: rs1566499503; hg19: chr14-20897984;