X-21655967-C-A

Position:

• chrX-21655967-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_153270.3(KLHL34):​c.1822G>T​(p.Ala608Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000082 in 1,097,400 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 5 hem.)
• Consequence: KLHL34 NM_153270.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.553

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.082521915).
• BS2: High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL34	NM_153270.3	c.1822G>T	p.Ala608Ser	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.1822G>T	p.Ala608Ser	missense_variant	1/1	6	NM_153270.3	ENSP00000368813.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000820 AC: 9 AN: 1097400 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 362988

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: 0.0000107

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

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

Nov 16, 2021

The c.1822G>T (p.A608S) alteration is located in exon 1 (coding exon 1) of the KLHL34 gene. This alteration results from a G to T substitution at nucleotide position 1822, causing the alanine (A) at amino acid position 608 to be replaced by a serine (S). 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	0.079
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.5
DANN	Benign	0.91
DEOGEN2	Benign	0.012	T
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.63	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.64	N
REVEL	Benign	0.059
Sift	Benign	0.49	T
Sift4G	Benign	0.76	T
Polyphen		0.0080	B
Vest4		0.043
MutPred		0.46		Loss of catalytic residue at A608 (P = 0.0216);
MVP		0.88
MPC		0.40
ClinPred		0.097	T
GERP RS		3.5
Varity_R		0.087
gMVP		0.21

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: rs1219147594; hg19: chrX-21674085;