rs9326114

Variant names:

• chr1-74489385-T-G
• rs9326114
• NM_001382280.1:c.-26-6010A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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:42952): (FPGT-TNNI3K readthrough) Enables protein C-terminus binding activity; protein kinase activity; and troponin I binding activity. Involved in protein phosphorylation and regulation of heart contraction. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
LRRC53	NM_001382280.1	c.-26-6010A>C		intron_variant	Intron 1 of 4	ENST00000294635.5	NP_001369209.1
TNNI3K	NM_015978.3	c.2181+137T>G		intron_variant	Intron 22 of 24	ENST00000326637.8	NP_057062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC53	ENST00000294635.5	c.-26-6010A>C		intron_variant	Intron 1 of 4	5	NM_001382280.1	ENSP00000294635.4
TNNI3K	ENST00000326637.8	c.2181+137T>G		intron_variant	Intron 22 of 24	1	NM_015978.3	ENSP00000322251.3
FPGT-TNNI3K	ENST00000557284.7	c.2484+137T>G		intron_variant	Intron 24 of 26	2		ENSP00000450895.3
FPGT-TNNI3K	ENST00000648585.1	n.*2087+137T>G		intron_variant	Intron 27 of 29			ENSP00000497631.1

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

African (AFR) AF: 0.291 AC: 4464 AN: 15328

American (AMR) AF: 0.0407 AC: 537 AN: 13198

Ashkenazi Jewish (ASJ) AF: 0.0218 AC: 309 AN: 14188

East Asian (EAS) AF: 0.0396 AC: 1152 AN: 29124

South Asian (SAS) AF: 0.0560 AC: 1984 AN: 35448

European-Finnish (FIN) AF: 0.0225 AC: 918 AN: 40726

Middle Eastern (MID) AF: 0.0550 AC: 214 AN: 3894

European-Non Finnish (NFE) AF: 0.00920 AC: 4405 AN: 478698

Other (OTH) AF: 0.0390 AC: 1232 AN: 31608

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

African (AFR) AF: 0.275 AC: 11422 AN: 41492

American (AMR) AF: 0.0467 AC: 715 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3472

East Asian (EAS) AF: 0.0423 AC: 219 AN: 5174

South Asian (SAS) AF: 0.0651 AC: 314 AN: 4826

European-Finnish (FIN) AF: 0.0245 AC: 260 AN: 10620

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0101 AC: 688 AN: 68026

Other (OTH) AF: 0.0795 AC: 168 AN: 2112

Alfa AF: 0.0737 Hom.: 196

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

May 17, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.3
DANN	Benign	0.78
PhyloP100		-0.19
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: rs9326114; hg19: chr1-74955069; COSMIC: COSV53949718;