chr13-69719578-C-A

Variant names:

• chr13-69719578-C-A
• rs766360091
• NM_020866.3:c.1806G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020866.3(KLHL1):​c.1806G>T​(p.Leu602Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,608,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: KLHL1 NM_020866.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL1	NM_020866.3	c.1806G>T	p.Leu602Phe	missense_variant	Exon 9 of 11	ENST00000377844.9	NP_065917.1
KLHL1	NM_001286725.2	c.1623G>T	p.Leu541Phe	missense_variant	Exon 8 of 10		NP_001273654.1
KLHL1	XM_017020678.3	c.1287G>T	p.Leu429Phe	missense_variant	Exon 9 of 11		XP_016876167.1
KLHL1	XM_017020679.2	c.1137G>T	p.Leu379Phe	missense_variant	Exon 9 of 11		XP_016876168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL1	ENST00000377844.9	c.1806G>T	p.Leu602Phe	missense_variant	Exon 9 of 11	1	NM_020866.3	ENSP00000367075.4
KLHL1	ENST00000545028.2	c.1623G>T	p.Leu541Phe	missense_variant	Exon 8 of 10	2		ENSP00000439602.2

Frequencies

GnomAD3 genomes AF: 0.00000669 AC: 1 AN: 149542 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.00000808 AC: 2 AN: 247514 AF XY: 0.00

Gnomad AFR exome AF: 0.0000640

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458578 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 725744

African (AFR) AF: 0.00 AC: 0 AN: 33372

American (AMR) AF: 0.00 AC: 0 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1109488

Other (OTH) AF: 0.00 AC: 0 AN: 60242

GnomAD4 genome AF: 0.00000669 AC: 1 AN: 149542 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 72950

African (AFR) AF: 0.00 AC: 0 AN: 39696

American (AMR) AF: 0.00 AC: 0 AN: 14958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67638

Other (OTH) AF: 0.00 AC: 0 AN: 2056

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1806G>T (p.L602F) alteration is located in exon 9 (coding exon 9) of the KLHL1 gene. This alteration results from a G to T substitution at nucleotide position 1806, causing the leucine (L) at amino acid position 602 to be replaced by a phenylalanine (F). 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	0.92
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.3	M;.
PhyloP100		1.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.5	D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.59		Gain of catalytic residue at L598 (P = 2e-04);.;
MVP		0.87
MPC		0.39
ClinPred		0.96	D
GERP RS		0.45
Varity_R		0.67
gMVP		0.58
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs766360091; hg19: chr13-70293710;