1-74470690-A-G

Variant names:

• chr1-74470690-A-G
• rs596204
• NM_001382280.1:c.2932T>C

Variant summary

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

The NM_001382280.1(LRRC53):​c.2932T>C​(p.Ser978Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 400,350 control chromosomes in the GnomAD database, including 88,085 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.69 (37961 hom., cov: 31)
  • Exomes 𝑓: 0.63 (50124 hom.)
• Consequence: LRRC53 NM_001382280.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.346
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3781781E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC53	NM_001382280.1	c.2932T>C	p.Ser978Pro	missense_variant	Exon 5 of 5	ENST00000294635.5	NP_001369209.1
TNNI3K	NM_015978.3	c.2121+7140A>G		intron_variant	Intron 21 of 24	ENST00000326637.8	NP_057062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC53	ENST00000294635.5	c.2932T>C	p.Ser978Pro	missense_variant	Exon 5 of 5	5	NM_001382280.1	ENSP00000294635.4
TNNI3K	ENST00000326637.8	c.2121+7140A>G		intron_variant	Intron 21 of 24	1	NM_015978.3	ENSP00000322251.3
FPGT-TNNI3K	ENST00000557284.7	c.2424+7140A>G		intron_variant	Intron 23 of 26	2		ENSP00000450895.3
FPGT-TNNI3K	ENST00000648585.1	n.*2027+7140A>G		intron_variant	Intron 26 of 29			ENSP00000497631.1

Frequencies

GnomAD3 genomes AF: 0.694 AC: 105284 AN: 151810 Hom.: 37900 Cov.: 31

Gnomad AFR AF: 0.891

Gnomad AMI AF: 0.550

Gnomad AMR AF: 0.691

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.859

Gnomad SAS AF: 0.662

Gnomad FIN AF: 0.627

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.672

GnomAD2 exomes AF: 0.549 AC: 201 AN: 366 AF XY: 0.495

Gnomad AFR exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad NFE exome AF: 0.537

Gnomad OTH exome AF: 0.800

GnomAD4 exome AF: 0.628 AC: 155890 AN: 248422 Hom.: 50124 Cov.: 0 AF XY: 0.623 AC XY: 78471 AN XY: 125858

African (AFR) AF: 0.891 AC: 6465 AN: 7252

American (AMR) AF: 0.695 AC: 5172 AN: 7442

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 5379 AN: 9242

East Asian (EAS) AF: 0.867 AC: 19847 AN: 22890

South Asian (SAS) AF: 0.637 AC: 1990 AN: 3122

European-Finnish (FIN) AF: 0.630 AC: 13110 AN: 20822

Middle Eastern (MID) AF: 0.660 AC: 1930 AN: 2926

European-Non Finnish (NFE) AF: 0.577 AC: 91333 AN: 158168

Other (OTH) AF: 0.644 AC: 10664 AN: 16558

GnomAD4 genome AF: 0.694 AC: 105401 AN: 151928 Hom.: 37961 Cov.: 31 AF XY: 0.697 AC XY: 51705 AN XY: 74222

African (AFR) AF: 0.891 AC: 36964 AN: 41498

American (AMR) AF: 0.691 AC: 10557 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 2027 AN: 3468

East Asian (EAS) AF: 0.858 AC: 4424 AN: 5156

South Asian (SAS) AF: 0.664 AC: 3195 AN: 4814

European-Finnish (FIN) AF: 0.627 AC: 6598 AN: 10516

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.582 AC: 39549 AN: 67908

Other (OTH) AF: 0.670 AC: 1404 AN: 2096

Alfa AF: 0.728 Hom.: 9443

Bravo AF: 0.710

TwinsUK AF: 0.593 AC: 2200

ALSPAC AF: 0.570 AC: 2197

ExAC AF: 0.413 AC: 900

Asia WGS AF: 0.757 AC: 2632 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.92
DANN	Benign	0.64
DEOGEN2	Benign	0.0016	T
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0000014	T
PhyloP100		-0.35
Sift4G	Benign	0.37	T
Vest4		0.023
GERP RS		2.1
Varity_R		0.072
gMVP		0.0045
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: rs596204; hg19: chr1-74936374; COSMIC: COSV53946744; COSMIC: COSV53946744;