X-21656756-G-C

Position:

• chrX-21656756-G-C

Variant summary

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

The NM_153270.3(KLHL34):​c.1033C>G​(p.Arg345Gly) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: KLHL34 NM_153270.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71

Genes affected

KLHL34 (HGNC:26634): (kelch like family member 34) Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

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=0.18232432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL34	NM_153270.3	c.1033C>G	p.Arg345Gly	missense_variant	1/1	ENST00000379499.3	NP_695002.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL34	ENST00000379499.3	c.1033C>G	p.Arg345Gly	missense_variant	1/1		NM_153270.3	ENSP00000368813	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

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

Jul 19, 2023

The c.1033C>G (p.R345G) alteration is located in exon 1 (coding exon 1) of the KLHL34 gene. This alteration results from a C to G substitution at nucleotide position 1033, causing the arginine (R) at amino acid position 345 to be replaced by a glycine (G). 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	0.12
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.20
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.046	D
Polyphen		0.12	B
Vest4		0.11
MutPred		0.43		Loss of MoRF binding (P = 0.0481);
MVP		0.94
MPC		0.58
ClinPred		0.33	T
GERP RS		3.2
Varity_R		0.24
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-21674874;