rs9326114

Positions:

• chr1-74489385-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001382280.1(LRRC53):​c.-26-6010A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0358 in 814,438 control chromosomes in the GnomAD database, including 2,509 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (1587 hom., cov: 32)
  • Exomes 𝑓: 0.023 (922 hom.)
• Consequence: LRRC53 NM_001382280.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.190

Genes affected

LRRC53 (HGNC:25255): (leucine rich repeat containing 53) Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TNNI3K (HGNC:19661): (TNNI3 interacting kinase) This gene encodes a protein that belongs to the MAP kinase kinase kinase (MAPKKK) family of protein kinases. The protein contains ankyrin repeat, protein kinase and serine-rich domains and is thought to play a role in cardiac physiology. [provided by RefSeq, Sep 2012]

FPGT-TNNI3K (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-74489385-T-G is Benign according to our data. Variant chr1-74489385-T-G is described in ClinVar as [Benign]. Clinvar id is 1290479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC53	NM_001382280.1	c.-26-6010A>C		intron_variant		ENST00000294635.5
TNNI3K	NM_015978.3	c.2181+137T>G		intron_variant		ENST00000326637.8
FPGT-TNNI3K	NM_001112808.3	c.2484+137T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC53	ENST00000294635.5	c.-26-6010A>C		intron_variant		5	NM_001382280.1	P1
TNNI3K	ENST00000326637.8	c.2181+137T>G		intron_variant		1	NM_015978.3	P1

Frequencies

GnomAD3 genomes AF: 0.0911 AC: 13859 AN: 152108 Hom.: 1573 Cov.: 32

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0469

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.0422

Gnomad SAS AF: 0.0646

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.0799

GnomAD4 exome AF: 0.0230 AC: 15215 AN: 662212 Hom.: 922 AF XY: 0.0232 AC XY: 7828 AN XY: 337178

Gnomad4 AFR exome AF: 0.291

Gnomad4 AMR exome AF: 0.0407

Gnomad4 ASJ exome AF: 0.0218

Gnomad4 EAS exome AF: 0.0396

Gnomad4 SAS exome AF: 0.0560

Gnomad4 FIN exome AF: 0.0225

Gnomad4 NFE exome AF: 0.00920

Gnomad4 OTH exome AF: 0.0390

GnomAD4 genome AF: 0.0914 AC: 13915 AN: 152226 Hom.: 1587 Cov.: 32 AF XY: 0.0901 AC XY: 6707 AN XY: 74432

Gnomad4 AFR AF: 0.275

Gnomad4 AMR AF: 0.0467

Gnomad4 ASJ AF: 0.0248

Gnomad4 EAS AF: 0.0423

Gnomad4 SAS AF: 0.0651

Gnomad4 FIN AF: 0.0245

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.0795

Alfa AF: 0.0680 Hom.: 176

Bravo AF: 0.101

Asia WGS AF: 0.0870 AC: 304 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.3
DANN	Benign	0.78

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

LitVar

Other links and lift over

dbSNP: rs9326114; hg19: chr1-74955069; COSMIC: COSV53949718;