4-39096755-A-G

Position:

• chr4-39096755-A-G

Variant summary

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

The NM_015990.5(KLHL5):​c.1177A>G​(p.Met393Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 7.29

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 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
KLHL5	NM_015990.5	c.1177A>G	p.Met393Val	missense_variant	6/11	ENST00000504108.7	NP_057074.4
LOC105374418	XR_925235.4	n.41-976T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL5	ENST00000504108.7	c.1177A>G	p.Met393Val	missense_variant	6/11	2	NM_015990.5	ENSP00000423897	A1
	ENST00000668468.1	n.270-27621T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jan 04, 2022

The c.1315A>G (p.M439V) alteration is located in exon 6 (coding exon 6) of the KLHL5 gene. This alteration results from a A to G substitution at nucleotide position 1315, causing the methionine (M) at amino acid position 439 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	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.037	.;.;T;.;.
Eigen	Benign	0.029
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.49	T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.2	.;.;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.6	N;N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.20	T;T;T;T;T
Sift4G	Benign	0.38	T;T;T;T;T
Polyphen		0.046, 0.30	.;.;B;B;.
Vest4		0.69
MutPred		0.39		.;.;Gain of ubiquitination at K443 (P = 0.078);Gain of ubiquitination at K443 (P = 0.078);.;
MVP		0.69
MPC		0.34
ClinPred		0.79	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1721103620; hg19: chr4-39098375;