22-20465153-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_032775.4(KLHL22):c.817G>A(p.Ala273Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,554 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: 0.0000041 (0 hom.)
• Consequence: KLHL22 NM_032775.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.43

Genes affected

KLHL22 (HGNC:25888): (kelch like family member 22) Enables 14-3-3 protein binding activity. Involved in several processes, including cellular protein metabolic process; cellular response to leucine; and mitotic spindle assembly checkpoint signaling. Located in several cellular components, including cytosol; intercellular bridge; and microtubule cytoskeleton. Part of Cul3-RING ubiquitin ligase complex. Colocalizes with lysosome and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

LOC124905085 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KLHL22
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL22	NM_032775.4	c.817G>A	p.Ala273Thr	missense_variant	4/7	ENST00000328879.9
LOC124905085	XR_007068014.1	n.132+4047C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL22	ENST00000328879.9	c.817G>A	p.Ala273Thr	missense_variant	4/7	1	NM_032775.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461554 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727108

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

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

Feb 15, 2023

The c.817G>A (p.A273T) alteration is located in exon 4 (coding exon 3) of the KLHL22 gene. This alteration results from a G to A substitution at nucleotide position 817, causing the alanine (A) at amino acid position 273 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	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.34	T;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.2	N;D
REVEL	Uncertain	0.58
Sift	Benign	0.088	T;T
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.67
MutPred		0.79		Gain of phosphorylation at A273 (P = 0.0996);.;
MVP		0.58
MPC		1.3
ClinPred		0.96	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
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: rs2053213502; hg19: chr22-20819440;