Variant X-87518029-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_019117.5(KLHL4):c.136A>T(p.Thr46Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00001 in 1,098,138 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000010 ( 0 hom. 2 hem. )

Consequence

KLHL4
NM_019117.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.06

Variant links:

Genes affected

KLHL4 (HGNC:6355): (kelch like family member 4) This gene encodes a member of the kelch family of proteins, which are characterized by kelch repeat motifs and a POZ/BTB protein-binding domain. It is thought that kelch repeats are actin binding domains. However, the specific function of this protein has not been determined. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

KLHL4 links:

KLHL4 (HGNC:):

KLHL4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12211773).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL4	NM_019117.5 linkuse as main transcript	c.136A>T	p.Thr46Ser	missense_variant	1/11	ENST00000373119.9	NP_061990.2	Q9C0H6-1A5PKX1
KLHL4	NM_057162.3 linkuse as main transcript	c.136A>T	p.Thr46Ser	missense_variant	1/11		NP_476503.1	Q9C0H6-2
KLHL4	XR_938403.3 linkuse as main transcript	n.228A>T		non_coding_transcript_exon_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KLHL4	ENST00000373119.9 linkuse as main transcript	c.136A>T	p.Thr46Ser	missense_variant	1/11	1	NM_019117.5	ENSP00000362211.4	Q9C0H6-1
KLHL4	ENST00000373114.4 linkuse as main transcript	c.136A>T	p.Thr46Ser	missense_variant	1/11	1		ENSP00000362206.4	Q9C0H6-2
KLHL4	ENST00000652270.1 linkuse as main transcript	n.136A>T		non_coding_transcript_exon_variant	1/12			ENSP00000498718.1	Q9C0H6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000273

AC:

AN:

183215

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67715

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000731

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:

0.0000122

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1098138

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

363522

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000569

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:

0.00000594

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

Cov.:

Alfa

AF:

0.000334

Hom.:

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

May 16, 2024

The c.136A>T (p.T46S) alteration is located in exon 1 (coding exon 1) of the KLHL4 gene. This alteration results from a A to T substitution at nucleotide position 136, causing the threonine (T) at amino acid position 46 to be replaced by a serine (S). 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

0.069

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.020

T;.

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.61

T;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.41

N;N

REVEL

Benign

0.22

Sift

Benign

0.22

T;T

Sift4G

Benign

0.68

T;T

Polyphen

0.017

B;B

Vest4

0.11

MutPred

0.15

Loss of glycosylation at T46 (P = 0.0254);Loss of glycosylation at T46 (P = 0.0254);

MVP

0.76

MPC

0.28

ClinPred

0.091

GERP RS

2.6

Varity_R

0.080

gMVP

0.21

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