X-21656695-C-T

Position:

• chrX-21656695-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_153270.3(KLHL34):​c.1094G>A​(p.Gly365Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000374 in 1,095,386 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000037 (0 hom. 10 hem.)
• Consequence: KLHL34 NM_153270.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.94

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 Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858
• BS2: High Hemizygotes in GnomAdExome4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL34	NM_153270.3	c.1094G>A	p.Gly365Asp	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.1094G>A	p.Gly365Asp	missense_variant	1/1	6	NM_153270.3	ENSP00000368813.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.00000578 AC: 1 AN: 173112 Hom.: 0 AF XY: 0.0000163 AC XY: 1 AN XY: 61390

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000131

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000374 AC: 41 AN: 1095386 Hom.: 0 Cov.: 31 AF XY: 0.0000277 AC XY: 10 AN XY: 361356

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: 0.0000476

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 24

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

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 04, 2024

The c.1094G>A (p.G365D) 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 1094, causing the glycine (G) at amino acid position 365 to be replaced by an aspartic acid (D). 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	0.38
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.4	L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.038	D
Polyphen		0.98	D
Vest4		0.75
MutPred		0.59		Gain of catalytic residue at G365 (P = 0.0345);
MVP		0.97
MPC		1.5
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.94
gMVP		0.87

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: rs761106271; hg19: chrX-21674813;