4-51995168-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001024611.3(LRRC66):​c.1854G>A​(p.Met618Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,614,242 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M618T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00028 ( 4 hom. )

Consequence

LRRC66
NM_001024611.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.320
Variant links:
Genes affected
LRRC66 (HGNC:34299): (leucine rich repeat containing 66) This gene encodes a protein belonging to the leucine-rich repeat family of proteins, which are involved in diverse biological processes, including cell adhesion, cellular trafficking, and hormone-receptor interactions. [provided by RefSeq, Apr 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0071442127).
BS2
High Homozygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LRRC66NM_001024611.3 linkc.1854G>A p.Met618Ile missense_variant Exon 5 of 5 ENST00000682860.1 NP_001019782.1 Q68CR7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LRRC66ENST00000682860.1 linkc.1854G>A p.Met618Ile missense_variant Exon 5 of 5 NM_001024611.3 ENSP00000508002.1 Q68CR7
LRRC66ENST00000343457.3 linkc.1854G>A p.Met618Ile missense_variant Exon 4 of 4 1 ENSP00000341944.3 Q68CR7

Frequencies

GnomAD3 genomes
AF:
0.000190
AC:
29
AN:
152234
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000250
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000357
AC:
89
AN:
249434
Hom.:
0
AF XY:
0.000443
AC XY:
60
AN XY:
135324
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00144
Gnomad FIN exome
AF:
0.0000464
Gnomad NFE exome
AF:
0.000336
Gnomad OTH exome
AF:
0.000495
GnomAD4 exome
AF:
0.000279
AC:
408
AN:
1461890
Hom.:
4
Cov.:
31
AF XY:
0.000336
AC XY:
244
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00159
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000209
Gnomad4 OTH exome
AF:
0.000414
GnomAD4 genome
AF:
0.000190
AC:
29
AN:
152352
Hom.:
0
Cov.:
32
AF XY:
0.000174
AC XY:
13
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000250
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000327
Hom.:
0
Bravo
AF:
0.000136
ESP6500AA
AF:
0.000256
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000347
AC:
42
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000654
EpiControl
AF:
0.000296

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 01, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1854G>A (p.M618I) alteration is located in exon 5 (coding exon 4) of the LRRC66 gene. This alteration results from a G to A substitution at nucleotide position 1854, causing the methionine (M) at amino acid position 618 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.61
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
0.57
DANN
Benign
0.47
DEOGEN2
Benign
0.0043
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.034
N
LIST_S2
Benign
0.43
T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.0071
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.63
N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.85
N
REVEL
Benign
0.018
Sift
Benign
0.35
T
Sift4G
Benign
0.61
T
Polyphen
0.015
B
Vest4
0.060
MutPred
0.17
Gain of glycosylation at S616 (P = 0.0136);
MVP
0.076
MPC
0.027
ClinPred
0.0080
T
GERP RS
0.20
Varity_R
0.084
gMVP
0.035

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs375054689; hg19: chr4-52861334; API