3-183499638-A-G

Position:

• chr3-183499638-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000341319.8(KLHL6):​c.1099T>C​(p.Trp367Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLHL6 ENST00000341319.8 missense
• Clinical Significance: - - O:1
• Conservation: PhyloP100: 8.87

Genes affected

KLHL6 (HGNC:18653): (kelch like family member 6) This gene encodes a member of the kelch-like (KLHL) family of proteins, which is involved in B-lymphocyte antigen receptor signaling and germinal-center B-cell maturation. The encoded protein contains an N-terminal broad-complex, tramtrack and bric a brac (BTB) domain that facilitates protein binding and dimerization, a BTB and C-terminal kelch (BACK) domain, and six C-terminal kelch repeat domains. Naturally occurring mutations in this gene are associated with chronic lymphocytic leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

KLHL6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL6	NM_130446.4	c.1099T>C	p.Trp367Arg	missense_variant	4/7	ENST00000341319.8	NP_569713.2
KLHL6	XM_011513273.4	c.718T>C	p.Trp240Arg	missense_variant	3/6		XP_011511575.1
KLHL6	XM_011513274.4	c.910-5357T>C		intron_variant			XP_011511576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL6	ENST00000341319.8	c.1099T>C	p.Trp367Arg	missense_variant	4/7	1	NM_130446.4	ENSP00000341342.3
KLHL6	ENST00000468734.1	n.1066T>C		non_coding_transcript_exon_variant	4/8	1		ENSP00000433734.1
KLHL6	ENST00000489245.5	n.922-5357T>C		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: -

Submissions summary: Other:1

Revision: -

Submissions by phenotype

Neoplasm Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.55		Gain of disorder (P = 0.0078);
MVP		0.69
MPC		1.0
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.66
gMVP		0.85

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: rs746332772; hg19: chr3-183217426;