4-39062839-T-G

Position:

• chr4-39062839-T-G

Variant summary

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

The NM_015990.5(KLHL5):​c.187T>G​(p.Leu63Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KLHL5 NM_015990.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37

Genes affected

KLHL5 (HGNC:6356): (kelch like family member 5) Predicted to enable actin binding activity. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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=0.17039609).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL5	NM_015990.5	c.187T>G	p.Leu63Val	missense_variant	1/11	ENST00000504108.7	NP_057074.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL5	ENST00000504108.7	c.187T>G	p.Leu63Val	missense_variant	1/11	2	NM_015990.5	ENSP00000423897	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461850 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727228

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

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 18, 2023

The c.325T>G (p.L109V) alteration is located in exon 1 (coding exon 1) of the KLHL5 gene. This alteration results from a T to G substitution at nucleotide position 325, causing the leucine (L) at amino acid position 109 to be replaced by a valine (V). 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	0.063
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.72
DEOGEN2	Benign	0.012	.;T;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.5	.;L;L;L
MutationTaster	Benign	0.53	D;D;D;D;D;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.060	N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.62	T;T;T;T
Sift4G	Benign	0.54	T;T;T;T
Polyphen		0.020, 0.082	.;B;B;.
Vest4		0.35
MutPred		0.32		.;Loss of catalytic residue at L109 (P = 0.059);Loss of catalytic residue at L109 (P = 0.059);Loss of catalytic residue at L109 (P = 0.059);
MVP		0.69
MPC		0.35
ClinPred		0.13	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.050
gMVP		0.28

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: rs1717554981; hg19: chr4-39064459;