13-69882324-T-C

Position:

• chr13-69882324-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020866.3(KLHL1):​c.1186A>G​(p.Met396Val) 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 benign outcome for this variant. 15/21 in silico tools predict a benign 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: 3.35

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20593706).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL1	NM_020866.3	c.1186A>G	p.Met396Val	missense_variant	5/11	ENST00000377844.9	NP_065917.1
KLHL1	NM_001286725.2	c.1003A>G	p.Met335Val	missense_variant	4/10		NP_001273654.1
KLHL1	XM_017020678.3	c.667A>G	p.Met223Val	missense_variant	5/11		XP_016876167.1
KLHL1	XM_017020679.2	c.517A>G	p.Met173Val	missense_variant	5/11		XP_016876168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL1	ENST00000377844.9	c.1186A>G	p.Met396Val	missense_variant	5/11	1	NM_020866.3	ENSP00000367075	P1
KLHL1	ENST00000545028.2	c.1003A>G	p.Met335Val	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

May 04, 2022

The c.1186A>G (p.M396V) alteration is located in exon 5 (coding exon 5) of the KLHL1 gene. This alteration results from a A to G substitution at nucleotide position 1186, causing the methionine (M) at amino acid position 396 to be replaced by a valine (V). 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	0.061
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.76	N;.
MutationTaster	Benign	0.70	N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.094
Sift	Benign	0.28	T;.
Sift4G	Benign	0.28	T;T
Polyphen		0.0060	B;.
Vest4		0.16
MutPred		0.47		Gain of catalytic residue at S395 (P = 0.002);.;
MVP		0.64
MPC		0.066
ClinPred		0.70	D
GERP RS		4.9
Varity_R		0.31
gMVP		0.34

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: chr13-70456456;