NM_020866.3:c.2143A>C

Variant names:

• chr13-69707669-T-G
• rs1875686940
• NM_020866.3:c.2143A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020866.3(KLHL1):​c.2143A>C​(p.Asn715His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N715S) has been classified 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: 4.90
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL1	NM_020866.3	c.2143A>C	p.Asn715His	missense_variant	Exon 10 of 11	ENST00000377844.9	NP_065917.1
KLHL1	NM_001286725.2	c.1960A>C	p.Asn654His	missense_variant	Exon 9 of 10		NP_001273654.1
KLHL1	XM_017020678.3	c.1624A>C	p.Asn542His	missense_variant	Exon 10 of 11		XP_016876167.1
KLHL1	XM_017020679.2	c.1474A>C	p.Asn492His	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	c.2143A>C	p.Asn715His	missense_variant	Exon 10 of 11	1	NM_020866.3	ENSP00000367075.4
KLHL1	ENST00000545028.2	c.1960A>C	p.Asn654His	missense_variant	Exon 9 of 10	2		ENSP00000439602.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2143A>C (p.N715H) alteration is located in exon 10 (coding exon 10) of the KLHL1 gene. This alteration results from a A to C substitution at nucleotide position 2143, causing the asparagine (N) at amino acid position 715 to be replaced by a histidine (H). 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	0.14
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.1	M;.
PhyloP100		4.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.5	N;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.0080	D;.
Sift4G	Uncertain	0.018	D;D
Polyphen		0.99	D;.
Vest4		0.52
MutPred		0.60		Gain of catalytic residue at Q711 (P = 0.0019);.;
MVP		0.94
MPC		0.11
ClinPred		0.91	D
GERP RS		5.2
Varity_R		0.27
gMVP		0.58
Mutation Taster		=62/38	polymorphism

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: rs1875686940; hg19: chr13-70281801;