3-47330132-G-A

Position:

• chr3-47330132-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_025010.5(KLHL18):​c.583G>A​(p.Val195Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000062 (0 hom.)
• Consequence: KLHL18 NM_025010.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.14

Genes affected

KLHL18 (HGNC:29120): (kelch like family member 18) Involved in positive regulation of mitotic cell cycle phase transition and protein ubiquitination. [provided by Alliance of Genome Resources, Apr 2022]

KLHL18 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26634783).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL18	NM_025010.5	c.583G>A	p.Val195Ile	missense_variant	4/10	ENST00000232766.6	NP_079286.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL18	ENST00000232766.6	c.583G>A	p.Val195Ile	missense_variant	4/10	1	NM_025010.5	ENSP00000232766.5
KLHL18	ENST00000442272.1	n.*272G>A		non_coding_transcript_exon_variant	3/9	2		ENSP00000392507.1
KLHL18	ENST00000461084.5	n.603G>A		non_coding_transcript_exon_variant	4/7	2
KLHL18	ENST00000442272.1	n.*272G>A		3_prime_UTR_variant	3/9	2		ENSP00000392507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727242

Gnomad4 AFR exome AF: 0.000179

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: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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 26, 2022

The c.583G>A (p.V195I) alteration is located in exon 4 (coding exon 4) of the KLHL18 gene. This alteration results from a G to A substitution at nucleotide position 583, causing the valine (V) at amino acid position 195 to be replaced by an isoleucine (I). 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	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.0074
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.19
Sift	Benign	0.046	D
Sift4G	Benign	0.19	T
Polyphen		0.10	B
Vest4		0.21
MutPred		0.76		Gain of helix (P = 0.062);
MVP		0.40
MPC		0.53
ClinPred		0.73	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.083
gMVP		0.33

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: rs1049051139; hg19: chr3-47371622;