chr3-47333212-A-G

Position:

• chr3-47333212-A-G

Variant summary

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

The NM_025010.5(KLHL18):​c.656A>G​(p.Tyr219Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KLHL18 NM_025010.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.32

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 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=0.2339896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL18	NM_025010.5	c.656A>G	p.Tyr219Cys	missense_variant	5/10	ENST00000232766.6	NP_079286.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL18	ENST00000232766.6	c.656A>G	p.Tyr219Cys	missense_variant	5/10	1	NM_025010.5	ENSP00000232766.5
KLHL18	ENST00000442272.1	n.*345A>G		non_coding_transcript_exon_variant	4/9	2		ENSP00000392507.1
KLHL18	ENST00000461084.5	n.676A>G		non_coding_transcript_exon_variant	5/7	2
KLHL18	ENST00000442272.1	n.*345A>G		3_prime_UTR_variant	4/9	2		ENSP00000392507.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.15
Sift	Benign	0.24	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.63		Gain of catalytic residue at P218 (P = 0.0078);
MVP		0.26
MPC		0.75
ClinPred		0.22	T
GERP RS		1.4
Varity_R		0.088
gMVP		0.34

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: rs1282993646; hg19: chr3-47374702;