Genetic Variant KEAP1:p.Val420Ile (chr19-10491644-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_203500.2(KEAP1):c.1258G>A(p.Val420Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V420L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KEAP1
NM_203500.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.13

Publications

1 publications found

Variant links:

Genes affected

KEAP1 (HGNC:23177): (kelch like ECH associated protein 1) This gene encodes a protein containing KELCH-1 like domains, as well as a BTB/POZ domain. Kelch-like ECH-associated protein 1 interacts with NF-E2-related factor 2 in a redox-sensitive manner and the dissociation of the proteins in the cytoplasm is followed by transportation of NF-E2-related factor 2 to the nucleus. This interaction results in the expression of the catalytic subunit of gamma-glutamylcysteine synthetase. Two alternatively spliced transcript variants encoding the same isoform have been found for this gene. [provided by RefSeq, Jul 2008]

KEAP1 Gene-Disease associations (from GenCC):

goiter, multinodular 1, with or without Sertoli-Leydig cell tumors
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KEAP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203500.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KEAP1	NM_203500.2	MANE Select	c.1258G>A	p.Val420Ile	missense	Exon 3 of 6	NP_987096.1	Q14145
	KEAP1	NM_012289.4		c.1258G>A	p.Val420Ile	missense	Exon 3 of 6	NP_036421.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KEAP1	ENST00000171111.10	TSL:1 MANE Select	c.1258G>A	p.Val420Ile	missense	Exon 3 of 6	ENSP00000171111.4	Q14145
KEAP1	ENST00000393623.6	TSL:1	c.1258G>A	p.Val420Ile	missense	Exon 3 of 6	ENSP00000377245.1	Q14145
KEAP1	ENST00000592478.5	TSL:1	c.76G>A	p.Val26Ile	missense	Exon 1 of 3	ENSP00000468014.1	K7EQX2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1441834

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715894

African (AFR)

AF:

0.00

AC:

AN:

32976

American (AMR)

AF:

0.00

AC:

AN:

41700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24728

East Asian (EAS)

AF:

0.00

AC:

AN:

39568

South Asian (SAS)

AF:

0.00

AC:

AN:

82978

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51972

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102734

Other (OTH)

AF:

0.00

AC:

AN:

59520

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.094

MetaRNN

Uncertain

0.50

MetaSVM

Uncertain

0.098

MutationAssessor

Uncertain

2.4

PhyloP100

6.1

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.95

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.014

Polyphen

0.43

Vest4

0.37

MutPred

0.72

Loss of catalytic residue at V420 (P = 0.2067)

MVP

0.80

MPC

0.86

ClinPred

0.84

GERP RS

5.6

PromoterAI

0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.52

gMVP

0.25

Mutation Taster

=67/33

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over