X-87518198-C-G

Position:

• chrX-87518198-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000373119.9(KLHL4):​c.305C>G​(p.Ala102Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,258 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 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: 0.0000018 (0 hom. 1 hem.)
• Consequence: KLHL4 ENST00000373119.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.959

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09489018).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL4	NM_019117.5	c.305C>G	p.Ala102Gly	missense_variant	1/11	ENST00000373119.9	NP_061990.2
KLHL4	NM_057162.3	c.305C>G	p.Ala102Gly	missense_variant	1/11		NP_476503.1
KLHL4	XR_938403.3	n.397C>G		non_coding_transcript_exon_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL4	ENST00000373119.9	c.305C>G	p.Ala102Gly	missense_variant	1/11	1	NM_019117.5	ENSP00000362211	P1
KLHL4	ENST00000373114.4	c.305C>G	p.Ala102Gly	missense_variant	1/11	1		ENSP00000362206
KLHL4	ENST00000652270.1	c.305C>G	p.Ala102Gly	missense_variant, NMD_transcript_variant	1/12			ENSP00000498718

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097258 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362650

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: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

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

Aug 02, 2022

The c.305C>G (p.A102G) alteration is located in exon 1 (coding exon 1) of the KLHL4 gene. This alteration results from a C to G substitution at nucleotide position 305, causing the alanine (A) at amino acid position 102 to be replaced by a glycine (G). 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	0.076
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T;.
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.095	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.28	N;N
REVEL	Benign	0.21
Sift	Benign	0.34	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.0010	B;B
Vest4		0.14
MutPred		0.26		Loss of stability (P = 0.0259);Loss of stability (P = 0.0259);
MVP		0.11
MPC		0.28
ClinPred		0.24	T
GERP RS		5.0
Varity_R		0.16
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

Other links and lift over

dbSNP: rs1235190045; hg19: chrX-86773201; COSMIC: COSV64148468;