Variant X-87632404-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_019117.5(KLHL4):c.1519C>T(p.Pro507Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000666 in 1,201,591 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.0000046 ( 0 hom. 2 hem. )

Consequence

KLHL4
NM_019117.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.59

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 -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.818

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL4	NM_019117.5 linkuse as main transcript	c.1519C>T	p.Pro507Ser	missense_variant	7/11	ENST00000373119.9	NP_061990.2	Q9C0H6-1A5PKX1
KLHL4	NM_057162.3 linkuse as main transcript	c.1519C>T	p.Pro507Ser	missense_variant	7/11		NP_476503.1	Q9C0H6-2
KLHL4	XR_938403.3 linkuse as main transcript	n.1611C>T		non_coding_transcript_exon_variant	7/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KLHL4	ENST00000373119.9 linkuse as main transcript	c.1519C>T	p.Pro507Ser	missense_variant	7/11	1	NM_019117.5	ENSP00000362211.4	Q9C0H6-1
KLHL4	ENST00000373114.4 linkuse as main transcript	c.1519C>T	p.Pro507Ser	missense_variant	7/11	1		ENSP00000362206.4	Q9C0H6-2
KLHL4	ENST00000652270.1 linkuse as main transcript	n.1519C>T		non_coding_transcript_exon_variant	7/12			ENSP00000498718.1	Q9C0H6-1

Frequencies

GnomAD3 genomes

AF:

0.0000269

AC:

AN:

111620

Hom.:

Cov.:

AF XY:

0.0000887

AC XY:

AN XY:

33806

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000165

AC:

AN:

182052

Hom.:

AF XY:

0.0000300

AC XY:

AN XY:

66676

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000369

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000459

AC:

AN:

1089971

Hom.:

Cov.:

AF XY:

0.00000562

AC XY:

AN XY:

355745

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000599

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000269

AC:

AN:

111620

Hom.:

Cov.:

AF XY:

0.0000887

AC XY:

AN XY:

33806

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000564

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000412

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

Mar 26, 2024

The c.1519C>T (p.P507S) alteration is located in exon 7 (coding exon 7) of the KLHL4 gene. This alteration results from a C to T substitution at nucleotide position 1519, causing the proline (P) at amino acid position 507 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

Uncertain

0.37

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

D;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Uncertain

0.042

MutationAssessor

Benign

0.82

L;L

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Pathogenic

0.74

Sift

Benign

0.14

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.97

D;P

Vest4

0.76

MutPred

0.60

Loss of glycosylation at P507 (P = 0.0523);Loss of glycosylation at P507 (P = 0.0523);

MVP

0.60

MPC

0.97

ClinPred

0.68

GERP RS

5.3

Varity_R

0.55

gMVP

0.54

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