chrX-87517913-A-C

Variant summary

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

The ENST00000373119.9(KLHL4):ā€‹c.20A>Cā€‹(p.Lys7Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,091,865 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 23)
Exomes š‘“: 0.0000018 ( 0 hom. 0 hem. )

Consequence

KLHL4
ENST00000373119.9 missense

Scores

7
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.07
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]

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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
KLHL4NM_019117.5 linkuse as main transcriptc.20A>C p.Lys7Thr missense_variant 1/11 ENST00000373119.9 NP_061990.2
KLHL4NM_057162.3 linkuse as main transcriptc.20A>C p.Lys7Thr missense_variant 1/11 NP_476503.1
KLHL4XR_938403.3 linkuse as main transcriptn.112A>C non_coding_transcript_exon_variant 1/12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KLHL4ENST00000373119.9 linkuse as main transcriptc.20A>C p.Lys7Thr missense_variant 1/111 NM_019117.5 ENSP00000362211 P1Q9C0H6-1
KLHL4ENST00000373114.4 linkuse as main transcriptc.20A>C p.Lys7Thr missense_variant 1/111 ENSP00000362206 Q9C0H6-2
KLHL4ENST00000652270.1 linkuse as main transcriptc.20A>C p.Lys7Thr missense_variant, NMD_transcript_variant 1/12 ENSP00000498718 Q9C0H6-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD3 exomes
AF:
0.0000114
AC:
2
AN:
176194
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
61648
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000147
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000183
AC:
2
AN:
1091865
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
358387
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000664
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

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 submitterclinical testingAmbry GeneticsMar 20, 2024The c.20A>C (p.K7T) alteration is located in exon 1 (coding exon 1) of the KLHL4 gene. This alteration results from a A to C substitution at nucleotide position 20, causing the lysine (K) at amino acid position 7 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
0.70
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Pathogenic
0.24
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.061
T;.
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Pathogenic
0.34
D
MetaRNN
Uncertain
0.46
T;T
MetaSVM
Uncertain
0.74
D
MutationAssessor
Uncertain
2.3
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-0.95
N;N
REVEL
Pathogenic
0.78
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.38
MutPred
0.46
Loss of methylation at K7 (P = 0.0148);Loss of methylation at K7 (P = 0.0148);
MVP
0.98
MPC
1.1
ClinPred
0.88
D
GERP RS
4.8
Varity_R
0.64
gMVP
0.50

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.

Other links and lift over

dbSNP: rs746993319; hg19: chrX-86772916; API