15-85768090-G-A

Position:

• chr15-85768090-G-A

Variant summary

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

The NM_022480.4(KLHL25):​c.1721C>T​(p.Ser574Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KLHL25 NM_022480.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

KLHL25 (HGNC:25732): (kelch like family member 25) Involved in protein ubiquitination; regulation of translational initiation; and ubiquitin-dependent protein catabolic process. Located in cytoplasm. Part of Cul3-RING ubiquitin ligase complex. [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
KLHL25	NM_022480.4	c.1721C>T	p.Ser574Leu	missense_variant	2/3	ENST00000337975.6	NP_071925.2
KLHL25	XM_047432937.1	c.1721C>T	p.Ser574Leu	missense_variant	2/3		XP_047288893.1
KLHL25	XM_047432938.1	c.1721C>T	p.Ser574Leu	missense_variant	2/3		XP_047288894.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL25	ENST00000337975.6	c.1721C>T	p.Ser574Leu	missense_variant	2/3	1	NM_022480.4	ENSP00000336800.5
KLHL25	ENST00000559131.1	n.154-7079C>T		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727216

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

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

Jan 04, 2024

The c.1721C>T (p.S574L) alteration is located in exon 2 (coding exon 1) of the KLHL25 gene. This alteration results from a C to T substitution at nucleotide position 1721, causing the serine (S) at amino acid position 574 to be replaced by a leucine (L). 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	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.051	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.043	D
Polyphen		0.0060	B
Vest4		0.82
MutPred		0.50		Loss of glycosylation at S574 (P = 0.0023);
MVP		0.49
MPC		0.38
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.23
gMVP		0.52

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: rs2089636581; hg19: chr15-86311321;