chr19-10491504-A-C

Variant names:

• chr19-10491504-A-C
• rs11085735
• NM_203500.2:c.1325+73T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_203500.2(KEAP1):​c.1325+73T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.929 in 1,290,536 control chromosomes in the GnomAD database, including 557,405 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.92 (64654 hom., cov: 31)
  • Exomes 𝑓: 0.93 (492751 hom.)
• Consequence: KEAP1 NM_203500.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• Publications: 29 publications found

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 Gene-Disease associations (from GenCC):

• goiter, multinodular 1, with or without Sertoli-Leydig cell tumors

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203500.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KEAP1	NM_203500.2	MANE Select	c.1325+73T>G		intron	N/A	NP_987096.1	Q14145
	KEAP1	NM_012289.4		c.1325+73T>G		intron	N/A	NP_036421.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KEAP1	ENST00000171111.10	TSL:1 MANE Select	c.1325+73T>G		intron	N/A	ENSP00000171111.4	Q14145
	KEAP1	ENST00000393623.6	TSL:1	c.1325+73T>G		intron	N/A	ENSP00000377245.1	Q14145
	KEAP1	ENST00000592478.5	TSL:1	c.143+73T>G		intron	N/A	ENSP00000468014.1	K7EQX2

Frequencies

GnomAD3 genomes AF: 0.921 AC: 140043 AN: 152022 Hom.: 64601 Cov.: 31

Gnomad AFR AF: 0.877

Gnomad AMI AF: 0.957

Gnomad AMR AF: 0.937

Gnomad ASJ AF: 0.912

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.971

Gnomad FIN AF: 0.943

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.929

GnomAD4 exome AF: 0.930 AC: 1058866 AN: 1138396 Hom.: 492751 AF XY: 0.931 AC XY: 520362 AN XY: 559110

African (AFR) AF: 0.875 AC: 22027 AN: 25172

American (AMR) AF: 0.957 AC: 20514 AN: 21428

Ashkenazi Jewish (ASJ) AF: 0.912 AC: 15769 AN: 17290

East Asian (EAS) AF: 1.00 AC: 34002 AN: 34016

South Asian (SAS) AF: 0.971 AC: 52563 AN: 54144

European-Finnish (FIN) AF: 0.941 AC: 36049 AN: 38326

Middle Eastern (MID) AF: 0.928 AC: 3001 AN: 3234

European-Non Finnish (NFE) AF: 0.926 AC: 830867 AN: 897294

Other (OTH) AF: 0.928 AC: 44074 AN: 47492

GnomAD4 genome AF: 0.921 AC: 140154 AN: 152140 Hom.: 64654 Cov.: 31 AF XY: 0.924 AC XY: 68703 AN XY: 74368

African (AFR) AF: 0.877 AC: 36409 AN: 41500

American (AMR) AF: 0.937 AC: 14295 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.912 AC: 3167 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5166 AN: 5168

South Asian (SAS) AF: 0.971 AC: 4683 AN: 4822

European-Finnish (FIN) AF: 0.943 AC: 10006 AN: 10606

Middle Eastern (MID) AF: 0.908 AC: 267 AN: 294

European-Non Finnish (NFE) AF: 0.931 AC: 63324 AN: 67998

Other (OTH) AF: 0.929 AC: 1964 AN: 2114

Alfa AF: 0.928 Hom.: 109883

Bravo AF: 0.918

Asia WGS AF: 0.977 AC: 3397 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.79
DANN	Benign	0.38
PhyloP100		-1.1
PromoterAI		-0.044	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11085735; hg19: chr19-10602180;