13-69838986-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020866.3(KLHL1):c.1404T>A(p.Asp468Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL1 NM_020866.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.345

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL1	NM_020866.3	c.1404T>A	p.Asp468Glu	missense_variant	6/11	ENST00000377844.9
KLHL1	NM_001286725.2	c.1221T>A	p.Asp407Glu	missense_variant	5/10
KLHL1	XM_017020678.3	c.885T>A	p.Asp295Glu	missense_variant	6/11
KLHL1	XM_017020679.2	c.735T>A	p.Asp245Glu	missense_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL1	ENST00000377844.9	c.1404T>A	p.Asp468Glu	missense_variant	6/11	1	NM_020866.3	P1
KLHL1	ENST00000545028.2	c.1221T>A	p.Asp407Glu	missense_variant	5/10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2023

The c.1404T>A (p.D468E) alteration is located in exon 6 (coding exon 6) of the KLHL1 gene. This alteration results from a T to A substitution at nucleotide position 1404, causing the aspartic acid (D) at amino acid position 468 to be replaced by a glutamic acid (E). 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	0.99
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	0.81	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.1	D;.
REVEL	Uncertain	0.62
Sift	Benign	0.062	T;.
Sift4G	Uncertain	0.052	T;T
Polyphen		0.97	D;.
Vest4		0.63
MutPred		0.39		Gain of catalytic residue at G466 (P = 5e-04);.;
MVP		0.84
MPC		0.26
ClinPred		0.98	D
GERP RS		2.4
Varity_R		0.21
gMVP		0.29

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.

Other links and lift over

hg19: chr13-70413118;