19-10491583-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V440M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (1 hom.)
• Consequence: KEAP1 NM_203500.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.17

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KEAP1
• BP4: Computational evidence support a benign effect (MetaRNN=0.30663303).
• BS2: High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KEAP1	NM_203500.2	c.1319T>C	p.Val440Ala	missense_variant	3/6	ENST00000171111.10
KEAP1	NM_012289.4	c.1319T>C	p.Val440Ala	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KEAP1	ENST00000171111.10	c.1319T>C	p.Val440Ala	missense_variant	3/6	1	NM_203500.2	P1
KEAP1	ENST00000393623.6	c.1319T>C	p.Val440Ala	missense_variant	3/6	1		P1
KEAP1	ENST00000592478.5	c.140T>C	p.Val47Ala	missense_variant	1/3	1
KEAP1	ENST00000590593.1	c.299T>C	p.Val100Ala	missense_variant, NMD_transcript_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 151948 Hom.: 0 Cov.: 32

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: 10 AN: 188936 Hom.: 0 AF XY: 0.0000393 AC XY: 4 AN XY: 101718

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: 39 AN: 1390184 Hom.: 1 Cov.: 32 AF XY: 0.0000307 AC XY: 21 AN XY: 684368

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: 14 AN: 152066 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74316

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.: 0

Bravo AF: 0.000125

ExAC AF: 0.0000497 AC: 6

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

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	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.85	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
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	T
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

Other links and lift over

dbSNP: rs200170293; hg19: chr19-10602259;