13-69882370-C-A

Position:

• chr13-69882370-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020866.3(KLHL1):​c.1140G>T​(p.Met380Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 4.93

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL1	NM_020866.3	c.1140G>T	p.Met380Ile	missense_variant	5/11	ENST00000377844.9	NP_065917.1
KLHL1	NM_001286725.2	c.957G>T	p.Met319Ile	missense_variant	4/10		NP_001273654.1
KLHL1	XM_017020678.3	c.621G>T	p.Met207Ile	missense_variant	5/11		XP_016876167.1
KLHL1	XM_017020679.2	c.471G>T	p.Met157Ile	missense_variant	5/11		XP_016876168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL1	ENST00000377844.9	c.1140G>T	p.Met380Ile	missense_variant	5/11	1	NM_020866.3	ENSP00000367075	P1
KLHL1	ENST00000545028.2	c.957G>T	p.Met319Ile	missense_variant	4/10	2		ENSP00000439602

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

Apr 20, 2024

The c.1140G>T (p.M380I) alteration is located in exon 5 (coding exon 5) of the KLHL1 gene. This alteration results from a G to T substitution at nucleotide position 1140, causing the methionine (M) at amino acid position 380 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	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.54	D;.
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.80	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.5	D;.
REVEL	Uncertain	0.51
Sift	Benign	0.084	T;.
Sift4G	Benign	0.29	T;T
Polyphen		0.21	B;.
Vest4		0.56
MutPred		0.54		Gain of catalytic residue at F376 (P = 0.001);.;
MVP		0.79
MPC		0.080
ClinPred		0.85	D
GERP RS		5.0
Varity_R		0.43
gMVP		0.52

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: chr13-70456502;