1-173766205-C-G

Position:

• chr1-173766205-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014458.4(KLHL20):​c.1211C>G​(p.Thr404Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KLHL20 NM_014458.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.77

Genes affected

KLHL20 (HGNC:25056): (kelch like family member 20) The protein encoded by this gene is a member of the kelch family of proteins, which is characterized by a 44-56 amino acid repeat motif. The kelch motif appears in many different polypeptide contexts and contains multiple potential protein-protein contact sites. Members of this family are present both throughout the cell and extracellularly, with diverse activities. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL20	NM_014458.4	c.1211C>G	p.Thr404Arg	missense_variant	8/12	ENST00000209884.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL20	ENST00000209884.5	c.1211C>G	p.Thr404Arg	missense_variant	8/12	1	NM_014458.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	-0.17	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.23	T
Polyphen		0.12	B
Vest4		0.81
MutPred		0.74		Gain of phosphorylation at T401 (P = 0.0682);
MVP		0.86
MPC		2.1
ClinPred		0.88	D
GERP RS		5.5
Varity_R		0.92
gMVP		0.89

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: chr1-173735344;