Variant 8-123651588-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001081675.3(KLHL38):c.1339C>A(p.Arg447Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,579,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

KLHL38
NM_001081675.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.63

Variant links:

Genes affected

KLHL38 (HGNC:34435): (kelch like family member 38)

KLHL38 links:

ENSG00000253286 (HGNC:):

ENSG00000253286 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.42336842).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL38	NM_001081675.3 linkuse as main transcript	c.1339C>A	p.Arg447Ser	missense_variant	2/4	ENST00000684634.1	NP_001075144.2	Q2WGJ6
KLHL38	XM_047421744.1 linkuse as main transcript	c.1339C>A	p.Arg447Ser	missense_variant	2/4		XP_047277700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KLHL38	ENST00000684634.1 linkuse as main transcript	c.1339C>A	p.Arg447Ser	missense_variant	2/4		NM_001081675.3	ENSP00000508228.1	Q2WGJ6
KLHL38	ENST00000325995.7 linkuse as main transcript	c.1339C>A	p.Arg447Ser	missense_variant	1/3	1		ENSP00000321475.7	Q2WGJ6
ENSG00000253286	ENST00000524355.1 linkuse as main transcript	n.245-6661G>T		intron_variant		4
ENSG00000253286	ENST00000652905.1 linkuse as main transcript	n.176-14760G>T		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000317

AC:

AN:

220986

Hom.:

AF XY:

0.0000252

AC XY:

AN XY:

118934

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000533

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000410

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000193

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000154

AC:

AN:

1426964

Hom.:

Cov.:

AF XY:

0.0000170

AC XY:

AN XY:

706788

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000632

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000125

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.11e-7

Gnomad4 OTH exome

AF:

0.0000847

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000727

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2024

The c.1339C>A (p.R447S) alteration is located in exon 1 (coding exon 1) of the KLHL38 gene. This alteration results from a C to A substitution at nucleotide position 1339, causing the arginine (R) at amino acid position 447 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

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0045

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.027

MetaRNN

Benign

0.42

MetaSVM

Benign

-0.97

MutationAssessor

Benign

2.0

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.99

REVEL

Uncertain

0.34

Sift

Benign

0.13

Sift4G

Benign

0.27

Polyphen

0.010

Vest4

0.88

MVP

0.59

MPC

0.051

ClinPred

0.11

GERP RS

2.3

Varity_R

0.24

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over