Variant 13-69701716-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020866.3(KLHL1):c.2233A>G(p.Ile745Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,608,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

KLHL1
NM_020866.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.49

Variant links:

Genes affected

KLHL1 (HGNC:6352): (kelch like family member 1) The KLHL1 protein belongs to a family of actin-organizing proteins related to Drosophila Kelch (Nemes et al., 2000 [PubMed 10888605]).[supplied by OMIM, Feb 2010]

KLHL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10553777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KLHL1	NM_020866.3 linkuse as main transcript	c.2233A>G	p.Ile745Val	missense_variant	11/11	ENST00000377844.9
KLHL1	NM_001286725.2 linkuse as main transcript	c.2050A>G	p.Ile684Val	missense_variant	10/10
KLHL1	XM_017020678.3 linkuse as main transcript	c.1714A>G	p.Ile572Val	missense_variant	11/11
KLHL1	XM_017020679.2 linkuse as main transcript	c.1564A>G	p.Ile522Val	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL1	ENST00000377844.9 linkuse as main transcript	c.2233A>G	p.Ile745Val	missense_variant	11/11	1	NM_020866.3	P1
KLHL1	ENST00000545028.2 linkuse as main transcript	c.2050A>G	p.Ile684Val	missense_variant	10/10	2

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151644

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248984

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134840

show subpopulations

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:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1456992

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724830

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

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:

0.00000541

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151644

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74094

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.00000756

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 06, 2021

The c.2233A>G (p.I745V) alteration is located in exon 11 (coding exon 11) of the KLHL1 gene. This alteration results from a A to G substitution at nucleotide position 2233, causing the isoleucine (I) at amino acid position 745 to be replaced by a valine (V). 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

0.084

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.056

T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.031

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.0049

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.045

N;.

MutationTaster

Benign

0.95

D;D

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.35

N;.

REVEL

Benign

0.057

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;T

Polyphen

0.0030

B;.

Vest4

0.076

MutPred

0.54

Gain of catalytic residue at Q747 (P = 3e-04);.;

MVP

0.58

MPC

0.053

ClinPred

0.17

GERP RS

5.3

Varity_R

0.069

gMVP

0.26

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

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