1-74470690-A-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

10

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.346

Publications

6 publications found
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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
LRRC53NM_001382280.1 linkc.2932T>C p.Ser978Pro missense_variant Exon 5 of 5 ENST00000294635.5 NP_001369209.1
TNNI3KNM_015978.3 linkc.2121+7140A>G intron_variant Intron 21 of 24 ENST00000326637.8 NP_057062.1 Q59H18-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LRRC53ENST00000294635.5 linkc.2932T>C p.Ser978Pro missense_variant Exon 5 of 5 5 NM_001382280.1 ENSP00000294635.4 A6NM62
TNNI3KENST00000326637.8 linkc.2121+7140A>G intron_variant Intron 21 of 24 1 NM_015978.3 ENSP00000322251.3 Q59H18-2
FPGT-TNNI3KENST00000557284.7 linkc.2424+7140A>G intron_variant Intron 23 of 26 2 ENSP00000450895.3 V9GXZ4
FPGT-TNNI3KENST00000648585.1 linkn.*2027+7140A>G intron_variant Intron 26 of 29 ENSP00000497631.1 A0A3B3ITB1

Frequencies

GnomAD3 genomes
AF:
0.694
AC:
105284
AN:
151810
Hom.:
37900
Cov.:
31
show subpopulations
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
show subpopulations
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
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.493
Heterozygous variant carriers
0
4129
8258
12388
16517
20646
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
400
800
1200
1600
2000
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.694
AC:
105401
AN:
151928
Hom.:
37961
Cov.:
31
AF XY:
0.697
AC XY:
51705
AN XY:
74222
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
1524
3047
4571
6094
7618
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
804
1608
2412
3216
4020
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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

Publications

Other links and lift over

dbSNP: rs596204; hg19: chr1-74936374; COSMIC: COSV53946744; COSMIC: COSV53946744; API