1-74475689-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001382280.1(LRRC53):c.1026T>C(p.Ala342=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 713,948 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (5 hom.)
• Consequence: LRRC53 NM_001382280.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.02

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 1-74475689-A-G is Benign according to our data. Variant chr1-74475689-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1694518.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-74475689-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.02 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC53	NM_001382280.1	c.1026T>C	p.Ala342=	synonymous_variant	4/5	ENST00000294635.5
TNNI3K	NM_015978.3	c.2121+12139A>G		intron_variant		ENST00000326637.8
FPGT-TNNI3K	NM_001112808.3	c.2424+12139A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC53	ENST00000294635.5	c.1026T>C	p.Ala342=	synonymous_variant	4/5	5	NM_001382280.1	P1
TNNI3K	ENST00000326637.8	c.2121+12139A>G		intron_variant		1	NM_015978.3	P1

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 363 AN: 152086 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00219 AC: 321 AN: 146780 Hom.: 0 AF XY: 0.00209 AC XY: 165 AN XY: 79036

Gnomad AFR exome AF: 0.000895

Gnomad AMR exome AF: 0.00129

Gnomad ASJ exome AF: 0.00172

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000451

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00445

Gnomad OTH exome AF: 0.00119

GnomAD4 exome AF: 0.00293 AC: 1645 AN: 561744 Hom.: 5 Cov.: 0 AF XY: 0.00291 AC XY: 882 AN XY: 303034

Gnomad4 AFR exome AF: 0.000837

Gnomad4 AMR exome AF: 0.00111

Gnomad4 ASJ exome AF: 0.00202

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000224

Gnomad4 FIN exome AF: 0.00184

Gnomad4 NFE exome AF: 0.00437

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00238 AC: 363 AN: 152204 Hom.: 2 Cov.: 32 AF XY: 0.00222 AC XY: 165 AN XY: 74416

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.000852

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00397

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00352 Hom.: 2

Bravo AF: 0.00230

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

LRRC53: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	4.5
Dann	Benign	0.66

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: rs144258020; hg19: chr1-74941373;