19-10489684-T-C

Position:

• chr19-10489684-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_203500.2(KEAP1):​c.1495A>G​(p.Met499Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KEAP1 NM_203500.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.770

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.10107213).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KEAP1	NM_203500.2	c.1495A>G	p.Met499Val	missense_variant	4/6	ENST00000171111.10	NP_987096.1
KEAP1	NM_012289.4	c.1495A>G	p.Met499Val	missense_variant	4/6		NP_036421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KEAP1	ENST00000171111.10	c.1495A>G	p.Met499Val	missense_variant	4/6	1	NM_203500.2	ENSP00000171111.4
KEAP1	ENST00000393623.6	c.1495A>G	p.Met499Val	missense_variant	4/6	1		ENSP00000377245.1
KEAP1	ENST00000592478.5	c.313A>G	p.Met105Val	missense_variant	2/3	1		ENSP00000468014.1
KEAP1	ENST00000590593.1	n.303-316A>G		intron_variant		3		ENSP00000467601.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461816 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

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

Aug 13, 2021

The c.1495A>G (p.M499V) alteration is located in exon 4 (coding exon 3) of the KEAP1 gene. This alteration results from a A to G substitution at nucleotide position 1495, causing the methionine (M) at amino acid position 499 to be replaced by a valine (V). 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	0.079
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.75
DEOGEN2	Benign	0.30	T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.64	.;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.72	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.98	N;N
REVEL	Benign	0.053
Sift	Benign	0.50	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.0040	B;B
Vest4		0.22
MutPred		0.36		Gain of catalytic residue at M499 (P = 0.0084);Gain of catalytic residue at M499 (P = 0.0084);
MVP		0.49
MPC		0.99
ClinPred		0.022	T
GERP RS		2.3
Varity_R		0.16
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: chr19-10600360;