X-87613893-T-G

Position:

• chrX-87613893-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_019117.5(KLHL4):​c.439T>G​(p.Ser147Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,084,110 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 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. 0 hem.)
• Consequence: KLHL4 NM_019117.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.53

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046417475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL4	NM_019117.5	c.439T>G	p.Ser147Ala	missense_variant	2/11	ENST00000373119.9	NP_061990.2
KLHL4	NM_057162.3	c.439T>G	p.Ser147Ala	missense_variant	2/11		NP_476503.1
KLHL4	XR_938403.3	n.531T>G		non_coding_transcript_exon_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL4	ENST00000373119.9	c.439T>G	p.Ser147Ala	missense_variant	2/11	1	NM_019117.5	ENSP00000362211.4
KLHL4	ENST00000373114.4	c.439T>G	p.Ser147Ala	missense_variant	2/11	1		ENSP00000362206.4
KLHL4	ENST00000652270.1	n.439T>G		non_coding_transcript_exon_variant	2/12			ENSP00000498718.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1084110 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 351530

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: 0.00000240

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

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

Apr 13, 2022

The c.439T>G (p.S147A) alteration is located in exon 2 (coding exon 2) of the KLHL4 gene. This alteration results from a T to G substitution at nucleotide position 439, causing the serine (S) at amino acid position 147 to be replaced by an alanine (A). 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	0.061
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.14
DANN	Benign	0.39
DEOGEN2	Benign	0.017	T;.
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.31	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.046	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.20	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.56	N;N
REVEL	Benign	0.091
Sift	Benign	0.71	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.0	B;B
Vest4		0.064
MutPred		0.22		Loss of phosphorylation at S147 (P = 0.0284);Loss of phosphorylation at S147 (P = 0.0284);
MVP		0.17
MPC		0.23
ClinPred		0.031	T
GERP RS		-4.2
Varity_R		0.049
gMVP		0.12

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: rs919365827; hg19: chrX-86868896;