Variant 13-70107365-G-A 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.335C>T(p.Thr112Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,872 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KLHL1
NM_020866.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.960

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:

ATXN8OS (HGNC:):

ATXN8OS 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=0.11226201).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL1	NM_020866.3 linkuse as main transcript	c.335C>T	p.Thr112Ile	missense_variant	1/11	ENST00000377844.9	NP_065917.1	Q9NR64Q8TBJ7
KLHL1	NM_001286725.2 linkuse as main transcript	c.335C>T	p.Thr112Ile	missense_variant	1/10		NP_001273654.1	Q9NR64F5H1J3Q8TBJ7B7Z3I8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KLHL1	ENST00000377844.9 linkuse as main transcript	c.335C>T	p.Thr112Ile	missense_variant	1/11	1	NM_020866.3	ENSP00000367075.4	Q9NR64
KLHL1	ENST00000545028.2 linkuse as main transcript	c.335C>T	p.Thr112Ile	missense_variant	1/10	2		ENSP00000439602.2	F5H1J3
ATXN8OS	ENST00000414504.6 linkuse as main transcript	n.153G>A		non_coding_transcript_exon_variant	1/5	5
ATXN8OS	ENST00000665905.1 linkuse as main transcript	n.37G>A		non_coding_transcript_exon_variant	1/4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727238

show subpopulations

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Oct 20, 2024

The c.335C>T (p.T112I) alteration is located in exon 1 (coding exon 1) of the KLHL1 gene. This alteration results from a C to T substitution at nucleotide position 335, causing the threonine (T) at amino acid position 112 to be replaced by an isoleucine (I). 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

0.076

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.61

T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.55

N;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.61

N;.

REVEL

Benign

0.053

Sift

Benign

0.17

T;.

Sift4G

Benign

0.22

T;T

Polyphen

0.012

B;.

Vest4

0.092

MutPred

0.32

Loss of disorder (P = 0.019);Loss of disorder (P = 0.019);

MVP

0.77

MPC

0.065

ClinPred

0.055

GERP RS

2.0

Varity_R

0.041

gMVP

0.32

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over