chr13-69719486-A-G

Variant names:

• chr13-69719486-A-G
• NM_020866.3:c.1898T>C

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.1898T>C​(p.Met633Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KLHL1 NM_020866.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL1	NM_020866.3	c.1898T>C	p.Met633Thr	missense_variant	Exon 9 of 11	ENST00000377844.9	NP_065917.1
KLHL1	NM_001286725.2	c.1715T>C	p.Met572Thr	missense_variant	Exon 8 of 10		NP_001273654.1
KLHL1	XM_017020678.3	c.1379T>C	p.Met460Thr	missense_variant	Exon 9 of 11		XP_016876167.1
KLHL1	XM_017020679.2	c.1229T>C	p.Met410Thr	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.1898T>C	p.Met633Thr	missense_variant	Exon 9 of 11	1	NM_020866.3	ENSP00000367075.4
KLHL1	ENST00000545028.2	c.1715T>C	p.Met572Thr	missense_variant	Exon 8 of 10	2		ENSP00000439602.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1898T>C (p.M633T) alteration is located in exon 9 (coding exon 9) of the KLHL1 gene. This alteration results from a T to C substitution at nucleotide position 1898, causing the methionine (M) at amino acid position 633 to be replaced by a threonine (T). 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	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.7	H;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.2	D;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0050	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.99	D;.
Vest4		0.93
MutPred		0.77		Gain of catalytic residue at K635 (P = 0.0019);.;
MVP		0.97
MPC		0.29
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.70
gMVP		0.85
Mutation Taster		=33/67	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

hg19: chr13-70293618;