1-74470690-A-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001382280.1(LRRC53):​c.2932T>G​(p.Ser978Ala) variant causes a missense 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. 11/14 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: not found (cov: 31)
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.089301705).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382280.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC53	NM_001382280.1	MANE Select	c.2932T>G	p.Ser978Ala	missense	Exon 5 of 5	NP_001369209.1	A6NM62
	TNNI3K	NM_015978.3	MANE Select	c.2121+7140A>C		intron	N/A	NP_057062.1	Q59H18-2
	LRRC53	NM_001364666.2		c.2836T>G	p.Ser946Ala	missense	Exon 4 of 4	NP_001351595.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC53	ENST00000294635.5	TSL:5 MANE Select	c.2932T>G	p.Ser978Ala	missense	Exon 5 of 5	ENSP00000294635.4	A6NM62
	TNNI3K	ENST00000326637.8	TSL:1 MANE Select	c.2121+7140A>C		intron	N/A	ENSP00000322251.3	Q59H18-2
	FPGT-TNNI3K	ENST00000557284.7	TSL:2	c.2424+7140A>C		intron	N/A	ENSP00000450895.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.44
DANN	Benign	0.65
DEOGEN2	Benign	0.0016	T
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.089	T
PhyloP100		-0.35
Sift4G	Benign	0.62	T
Vest4		0.074
MVP		0.45
GERP RS		2.1
Varity_R		0.049
gMVP		0.00091
Mutation Taster		=92/8	polymorphism

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;