19-10491504-A-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_203500.2(KEAP1):​c.1325+73T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KEAP1 NM_203500.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KEAP1	NM_203500.2	c.1325+73T>A		intron_variant	Intron 3 of 5	ENST00000171111.10	NP_987096.1
KEAP1	NM_012289.4	c.1325+73T>A		intron_variant	Intron 3 of 5		NP_036421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KEAP1	ENST00000171111.10	c.1325+73T>A		intron_variant	Intron 3 of 5	1	NM_203500.2	ENSP00000171111.4
KEAP1	ENST00000393623.6	c.1325+73T>A		intron_variant	Intron 3 of 5	1		ENSP00000377245.1
KEAP1	ENST00000592478.5	c.143+73T>A		intron_variant	Intron 1 of 2	1		ENSP00000468014.1
KEAP1	ENST00000590593.1	n.302+73T>A		intron_variant	Intron 1 of 2	3		ENSP00000467601.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1139104 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 559454

African (AFR) AF: 0.00 AC: 0 AN: 25204

American (AMR) AF: 0.00 AC: 0 AN: 21436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17292

East Asian (EAS) AF: 0.00 AC: 0 AN: 34016

South Asian (SAS) AF: 0.00 AC: 0 AN: 54176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3234

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 897884

Other (OTH) AF: 0.00 AC: 0 AN: 47518

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.95
DANN	Benign	0.22
PhyloP100		-1.1
PromoterAI		-0.049	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs11085735; hg19: chr19-10602180;