19-10491583-A-G

Position:

chr19-10491583-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_203500.2(KEAP1):c.1319T>C(p.Val440Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000344 in 1,542,250 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 1 hom. )

Consequence

KEAP1
NM_203500.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.17

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KEAP1. . Gene score misZ 3.7962 (greater than the threshold 3.09). Trascript score misZ 4.2882 (greater than threshold 3.09). GenCC has associacion of gene with goiter, multinodular 1, with or without Sertoli-Leydig cell tumors.

BP4

Computational evidence support a benign effect (MetaRNN=0.30663303).

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KEAP1	NM_203500.2 linkuse as main transcript	c.1319T>C	p.Val440Ala	missense_variant	3/6	ENST00000171111.10	NP_987096.1	Q14145A0A024R7C0
KEAP1	NM_012289.4 linkuse as main transcript	c.1319T>C	p.Val440Ala	missense_variant	3/6		NP_036421.2	Q14145A0A024R7C0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KEAP1	ENST00000171111.10 linkuse as main transcript	c.1319T>C	p.Val440Ala	missense_variant	3/6	1	NM_203500.2	ENSP00000171111.4	Q14145
KEAP1	ENST00000393623.6 linkuse as main transcript	c.1319T>C	p.Val440Ala	missense_variant	3/6	1		ENSP00000377245.1	Q14145
KEAP1	ENST00000592478.5 linkuse as main transcript	c.137T>C	p.Val46Ala	missense_variant	1/3	1		ENSP00000468014.1	K7EQX2
KEAP1	ENST00000590593.1 linkuse as main transcript	n.296T>C		non_coding_transcript_exon_variant	1/3	3		ENSP00000467601.1	K7EPZ3

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

151948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000529

AC:

AN:

188936

Hom.:

AF XY:

0.0000393

AC XY:

AN XY:

101718

show subpopulations

Gnomad AFR exome

AF:

0.0000690

Gnomad AMR exome

AF:

0.000325

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1390184

Hom.:

Cov.:

AF XY:

0.0000307

AC XY:

AN XY:

684368

show subpopulations

Gnomad4 AFR exome

AF:

0.0000321

Gnomad4 AMR exome

AF:

0.000359

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000134

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000102

Gnomad4 OTH exome

AF:

0.0000525

GnomAD4 genome

AF:

0.0000921

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000459

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000435

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.0000497

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2023

The c.1319T>C (p.V440A) alteration is located in exon 3 (coding exon 2) of the KEAP1 gene. This alteration results from a T to C substitution at nucleotide position 1319, causing the valine (V) at amino acid position 440 to be replaced by an alanine (A). 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

0.27

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

D;D

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.80

.;T

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.31

T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

0.85

L;L

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.5

N;N

REVEL

Uncertain

0.40

Sift

Benign

0.041

D;D

Sift4G

Benign

0.23

T;T

Polyphen

0.017

B;B

Vest4

0.61

MutPred

0.79

Gain of disorder (P = 0.0493);Gain of disorder (P = 0.0493);

MVP

0.89

MPC

1.2

ClinPred

0.058

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.62

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over