Variant 13-69707759-G-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_020866.3(KLHL1):c.2053C>G(p.Pro685Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,460,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

KLHL1
NM_020866.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.57

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:

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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=0.32058632).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL1	NM_020866.3 link	c.2053C>G	p.Pro685Ala	missense_variant	Exon 10 of 11	ENST00000377844.9	NP_065917.1	Q9NR64Q8TBJ7
KLHL1	NM_001286725.2 link	c.1870C>G	p.Pro624Ala	missense_variant	Exon 9 of 10		NP_001273654.1	Q9NR64F5H1J3Q8TBJ7B7Z3I8
KLHL1	XM_017020678.3 link	c.1534C>G	p.Pro512Ala	missense_variant	Exon 10 of 11		XP_016876167.1
KLHL1	XM_017020679.2 link	c.1384C>G	p.Pro462Ala	missense_variant	Exon 10 of 11		XP_016876168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL1	ENST00000377844.9 link	c.2053C>G	p.Pro685Ala	missense_variant	Exon 10 of 11	1	NM_020866.3	ENSP00000367075.4		Q9NR64
KLHL1	ENST00000545028.2 link	c.1870C>G	p.Pro624Ala	missense_variant	Exon 9 of 10	2		ENSP00000439602.2		F5H1J3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250852

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135582

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460664

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726640

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000767

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:

0.0000663

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2053C>G (p.P685A) alteration is located in exon 10 (coding exon 10) of the KLHL1 gene. This alteration results from a C to G substitution at nucleotide position 2053, causing the proline (P) at amino acid position 685 to be replaced by an alanine (A). 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

0.17

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Benign

0.81

DEOGEN2

Benign

0.40

T;.

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.035

MetaRNN

Benign

0.32

T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.1

L;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.0

N;.

REVEL

Uncertain

0.36

Sift

Benign

0.58

T;.

Sift4G

Benign

0.58

T;T

Polyphen

0.20

B;.

Vest4

0.43

MutPred

0.47

Gain of catalytic residue at A684 (P = 0.0226);.;

MVP

0.88

MPC

0.26

ClinPred

0.49

GERP RS

5.4

Varity_R

0.11

gMVP

0.33

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