rs547713274

Variant names:

• chr19-10489756-C-A
• rs547713274
• NM_203500.2:c.1423G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-10489756-C-A
• chr19-10489756-C-G
• chr19-10489756-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_203500.2(KEAP1):​c.1423G>T​(p.Val475Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KEAP1 NM_203500.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.61

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KEAP1	NM_203500.2	c.1423G>T	p.Val475Leu	missense_variant	Exon 4 of 6	ENST00000171111.10	NP_987096.1
KEAP1	NM_012289.4	c.1423G>T	p.Val475Leu	missense_variant	Exon 4 of 6		NP_036421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KEAP1	ENST00000171111.10	c.1423G>T	p.Val475Leu	missense_variant	Exon 4 of 6	1	NM_203500.2	ENSP00000171111.4
KEAP1	ENST00000393623.6	c.1423G>T	p.Val475Leu	missense_variant	Exon 4 of 6	1		ENSP00000377245.1
KEAP1	ENST00000592478.5	c.241G>T	p.Val81Leu	missense_variant	Exon 2 of 3	1		ENSP00000468014.1
KEAP1	ENST00000590593.1	n.303-388G>T		intron_variant	Intron 1 of 2	3		ENSP00000467601.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;T
Eigen	Benign	0.17
Eigen_PC	Benign	0.058
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	-0.014	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.55
Sift	Benign	0.053	T;T
Sift4G	Uncertain	0.014	D;D
Polyphen		1.0	D;D
Vest4		0.39
MutPred		0.74		Loss of catalytic residue at V475 (P = 0.0208);Loss of catalytic residue at V475 (P = 0.0208);
MVP		0.82
MPC		2.0
ClinPred		0.84	D
GERP RS		3.7
Varity_R		0.32
gMVP		0.54

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

LitVar

Other links and lift over

dbSNP: rs547713274; hg19: chr19-10600432; COSMIC: COSV105847315; COSMIC: COSV105847315;