X-21656081-C-T

Position:

• chrX-21656081-C-T

Variant summary

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

The NM_153270.3(KLHL34):​c.1708G>A​(p.Glu570Lys) variant causes a missense change involving the alteration of a non-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: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: KLHL34 NM_153270.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.98

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 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
KLHL34	NM_153270.3	c.1708G>A	p.Glu570Lys	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.1708G>A	p.Glu570Lys	missense_variant	1/1		NM_153270.3	ENSP00000368813	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1073617 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 344253

Gnomad4 AFR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 23

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

Dec 28, 2022

The c.1708G>A (p.E570K) alteration is located in exon 1 (coding exon 1) of the KLHL34 gene. This alteration results from a G to A substitution at nucleotide position 1708, causing the glutamic acid (E) at amino acid position 570 to be replaced by a lysine (K). 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	Uncertain	0.54
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.93	N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.20
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.056	T
Polyphen		0.73	P
Vest4		0.41
MutPred		0.57		Gain of ubiquitination at E570 (P = 0.0337);
MVP		0.77
MPC		0.53
ClinPred		0.45	T
GERP RS		5.3
Varity_R		0.29
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-21674199;