Variant 1-6593579-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_014851.4(KLHL21):c.1580C>T(p.Ser527Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,498 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KLHL21
NM_014851.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60

Variant links:

Genes affected

KLHL21 (HGNC:29041): (kelch like family member 21) Enables cullin family protein binding activity. Contributes to ubiquitin-protein transferase activity. Involved in chromosome passenger complex localization to spindle midzone; protein ubiquitination; and regulation of cytokinesis. Located in polar microtubule. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

KLHL21 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL21	NM_014851.4 linkuse as main transcript	c.1580C>T	p.Ser527Leu	missense_variant	4/4	ENST00000377658.8	NP_055666.2	Q9UJP4-1
KLHL21	NM_001324309.2 linkuse as main transcript	c.*529C>T		3_prime_UTR_variant	4/4		NP_001311238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KLHL21	ENST00000377658.8 linkuse as main transcript	c.1580C>T	p.Ser527Leu	missense_variant	4/4	1	NM_014851.4	ENSP00000366886.4	Q9UJP4-1
KLHL21	ENST00000496707.5 linkuse as main transcript	c.479C>T	p.Ser160Leu	missense_variant	4/4	1		ENSP00000468710.1	K7ESH2
KLHL21	ENST00000377663.3 linkuse as main transcript	c.*1786C>T		3_prime_UTR_variant	3/3	1		ENSP00000366891.3	Q9UJP4-2
KLHL21	ENST00000467612.5 linkuse as main transcript	c.479C>T	p.Ser160Leu	missense_variant	4/4	3		ENSP00000466089.1	K7ELI0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250484

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135526

show subpopulations

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:

0.0000327

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461498

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727056

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000193

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The c.1580C>T (p.S527L) alteration is located in exon 4 (coding exon 4) of the KLHL21 gene. This alteration results from a C to T substitution at nucleotide position 1580, causing the serine (S) at amino acid position 527 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

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.089

T;T;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.73

D;D;D

MetaSVM

Benign

-0.54

MutationAssessor

Benign

0.93

L;.;.

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-2.3

N;.;.

REVEL

Uncertain

0.41

Sift

Uncertain

0.010

D;.;.

Sift4G

Uncertain

0.0020

D;T;.

Polyphen

1.0

D;.;.

Vest4

0.73

MVP

0.86

MPC

0.78

ClinPred

0.83

GERP RS

5.3

Varity_R

0.18

gMVP

0.58

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over