4-39081192-G-A

Position:

• chr4-39081192-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015990.5(KLHL5):​c.656G>A​(p.Gly219Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL5 NM_015990.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.16

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35008654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL5	NM_015990.5	c.656G>A	p.Gly219Asp	missense_variant	3/11	ENST00000504108.7	NP_057074.4
LOC105374418	XR_925235.4	n.67-12058C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL5	ENST00000504108.7	c.656G>A	p.Gly219Asp	missense_variant	3/11	2	NM_015990.5	ENSP00000423897	A1
	ENST00000668468.1	n.270-12058C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Mar 31, 2024

The c.794G>A (p.G265D) alteration is located in exon 3 (coding exon 3) of the KLHL5 gene. This alteration results from a G to A substitution at nucleotide position 794, causing the glycine (G) at amino acid position 265 to be replaced by an aspartic acid (D). 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	0.88
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;.;T;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.35	.;.;N;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.93	N;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.60	T;T;T;T;T
Sift4G	Benign	0.79	T;T;T;T;T
Polyphen		0.55, 0.81	.;.;P;P;.
Vest4		0.53
MutPred		0.68		.;.;Loss of catalytic residue at V266 (P = 0.0781);Loss of catalytic residue at V266 (P = 0.0781);.;
MVP		0.78
MPC		0.69
ClinPred		0.85	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.43

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: rs1196293003; hg19: chr4-39082812;