dbSNP rs529429039: KEAP1:p.Val440Met (chr19-10491584-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_203500.2(KEAP1):c.1318G>A(p.Val440Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000816 in 1,543,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V440A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

KEAP1
NM_203500.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.21

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 11 AD gene.

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.1318G>A	p.Val440Met	missense	Exon 3 of 6	NP_987096.1	Q14145
	KEAP1	NM_012289.4		c.1318G>A	p.Val440Met	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.1318G>A	p.Val440Met	missense	Exon 3 of 6	ENSP00000171111.4	Q14145
KEAP1	ENST00000393623.6	TSL:1	c.1318G>A	p.Val440Met	missense	Exon 3 of 6	ENSP00000377245.1	Q14145
KEAP1	ENST00000592478.5	TSL:1	c.136G>A	p.Val46Met	missense	Exon 1 of 3	ENSP00000468014.1	K7EQX2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000843

AC:

AN:

189734

AF XY:

0.0000880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000810

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000801

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000826

AC:

115

AN:

1391528

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

685234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31232

American (AMR)

AF:

0.0000595

AC:

AN:

33640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21652

East Asian (EAS)

AF:

0.00

AC:

AN:

39070

South Asian (SAS)

AF:

0.000707

AC:

AN:

74992

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50012

Middle Eastern (MID)

AF:

0.000781

AC:

AN:

5124

European-Non Finnish (NFE)

AF:

0.0000436

AC:

AN:

1078642

Other (OTH)

AF:

0.000157

AC:

AN:

57164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41588

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000827

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.000108

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.74

MetaSVM

Uncertain

0.41

MutationAssessor

Benign

1.6

PhyloP100

3.2

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.58

Sift

Uncertain

0.011

Sift4G

Uncertain

0.030

Polyphen

0.94

Vest4

0.70

MVP

0.94

MPC

1.7

ClinPred

0.14

GERP RS

5.7

PromoterAI

0.0060

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.41

gMVP

0.72

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over