Variant 13-69740531-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020866.3(KLHL1):c.1665T>G(p.Ile555Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,611,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

KLHL1
NM_020866.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.156

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06752294).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL1	NM_020866.3 linkuse as main transcript	c.1665T>G	p.Ile555Met	missense_variant	8/11	ENST00000377844.9	NP_065917.1	Q9NR64Q8TBJ7
KLHL1	NM_001286725.2 linkuse as main transcript	c.1482T>G	p.Ile494Met	missense_variant	7/10		NP_001273654.1	Q9NR64F5H1J3Q8TBJ7B7Z3I8
KLHL1	XM_017020678.3 linkuse as main transcript	c.1146T>G	p.Ile382Met	missense_variant	8/11		XP_016876167.1
KLHL1	XM_017020679.2 linkuse as main transcript	c.996T>G	p.Ile332Met	missense_variant	8/11		XP_016876168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL1	ENST00000377844.9 linkuse as main transcript	c.1665T>G	p.Ile555Met	missense_variant	8/11	1	NM_020866.3	ENSP00000367075.4		Q9NR64
KLHL1	ENST00000545028.2 linkuse as main transcript	c.1482T>G	p.Ile494Met	missense_variant	7/10	2		ENSP00000439602.2		F5H1J3

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

250800

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135566

show subpopulations

Gnomad AFR exome

AF:

0.000800

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1459756

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726230

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

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:

0.00

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.000256

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.000941

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000109

Hom.:

Bravo

AF:

0.000215

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

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

Sep 15, 2021

The c.1665T>G (p.I555M) alteration is located in exon 8 (coding exon 8) of the KLHL1 gene. This alteration results from a T to G substitution at nucleotide position 1665, causing the isoleucine (I) at amino acid position 555 to be replaced by a methionine (M). 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

0.12

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.26

CADD

Benign

9.3

DANN

Benign

0.94

DEOGEN2

Benign

0.33

T;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.068

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Uncertain

0.65

PROVEAN

Benign

1.4

N;.

REVEL

Uncertain

0.33

Sift

Benign

0.87

T;.

Sift4G

Benign

0.84

T;T

Polyphen

0.0

B;.

Vest4

0.42

MVP

0.60

MPC

0.072

ClinPred

0.036

GERP RS

-3.6

Varity_R

0.053

gMVP

0.49

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