chr19-10491629-T-A

Variant names:

• chr19-10491629-T-A
• NM_203500.2:c.1273A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_203500.2(KEAP1):​c.1273A>T​(p.Ile425Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KEAP1 NM_203500.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.76

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KEAP1	NM_203500.2	c.1273A>T	p.Ile425Phe	missense_variant	Exon 3 of 6	ENST00000171111.10	NP_987096.1
KEAP1	NM_012289.4	c.1273A>T	p.Ile425Phe	missense_variant	Exon 3 of 6		NP_036421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KEAP1	ENST00000171111.10	c.1273A>T	p.Ile425Phe	missense_variant	Exon 3 of 6	1	NM_203500.2	ENSP00000171111.4
KEAP1	ENST00000393623.6	c.1273A>T	p.Ile425Phe	missense_variant	Exon 3 of 6	1		ENSP00000377245.1
KEAP1	ENST00000592478.5	c.91A>T	p.Ile31Phe	missense_variant	Exon 1 of 3	1		ENSP00000468014.1
KEAP1	ENST00000590593.1	n.250A>T		non_coding_transcript_exon_variant	Exon 1 of 3	3		ENSP00000467601.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.86	P;P
Vest4		0.78
MutPred		0.60		Loss of sheet (P = 0.302);Loss of sheet (P = 0.302);
MVP		0.94
MPC		2.3
ClinPred		0.96	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.73
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-10602305;