7-102467403-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152892.3(LRWD1):ā€‹c.497A>Gā€‹(p.Gln166Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000706 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00013 ( 0 hom., cov: 31)
Exomes š‘“: 0.000065 ( 0 hom. )

Consequence

LRWD1
NM_152892.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.949
Variant links:
Genes affected
LRWD1 (HGNC:21769): (leucine rich repeats and WD repeat domain containing 1) The protein encoded by this gene interacts with components of the origin recognition complex (ORC) and regulates the formation of the prereplicative complex. The encoded protein stabilizes the ORC and therefore aids in DNA replication. This protein is required for the G1/S phase transition of the cell cycle. In addition, the encoded protein binds to trimethylated histone H3 in heterochromatin and recruits the ORC and lysine methyltransferases, which help maintain the repressive heterochromatic state. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.013233811).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LRWD1NM_152892.3 linkc.497A>G p.Gln166Arg missense_variant Exon 4 of 15 ENST00000292616.10 NP_690852.1 Q9UFC0A0A140VJD0
LRWD1NM_001317721.2 linkc.41A>G p.Gln14Arg missense_variant Exon 4 of 15 NP_001304650.1 Q9UFC0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LRWD1ENST00000292616.10 linkc.497A>G p.Gln166Arg missense_variant Exon 4 of 15 1 NM_152892.3 ENSP00000292616.5 Q9UFC0

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
151998
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
Gnomad ASJ
AF:
0.00404
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000152
AC:
38
AN:
250474
Hom.:
0
AF XY:
0.000170
AC XY:
23
AN XY:
135604
show subpopulations
Gnomad AFR exome
AF:
0.0000617
Gnomad AMR exome
AF:
0.0000869
Gnomad ASJ exome
AF:
0.00269
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000354
Gnomad OTH exome
AF:
0.000491
GnomAD4 exome
AF:
0.0000650
AC:
95
AN:
1461724
Hom.:
0
Cov.:
32
AF XY:
0.0000729
AC XY:
53
AN XY:
727150
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.00253
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.000265
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
151998
Hom.:
0
Cov.:
31
AF XY:
0.0000943
AC XY:
7
AN XY:
74226
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000197
Gnomad4 ASJ
AF:
0.00404
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000239
Hom.:
0
Bravo
AF:
0.000132
ExAC
AF:
0.000140
AC:
17
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 17, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.497A>G (p.Q166R) alteration is located in exon 4 (coding exon 4) of the LRWD1 gene. This alteration results from a A to G substitution at nucleotide position 497, causing the glutamine (Q) at amino acid position 166 to be replaced by an arginine (R). 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
0.067
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
12
DANN
Benign
0.92
DEOGEN2
Benign
0.0042
T;.
Eigen
Benign
-0.49
Eigen_PC
Benign
-0.40
FATHMM_MKL
Benign
0.70
D
LIST_S2
Benign
0.54
T;T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.013
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.3
L;.
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.51
N;.
REVEL
Benign
0.036
Sift
Benign
0.24
T;.
Sift4G
Benign
0.66
T;T
Polyphen
0.0010
B;.
Vest4
0.13
MutPred
0.23
Gain of MoRF binding (P = 0.0408);.;
MVP
0.66
MPC
0.053
ClinPred
0.013
T
GERP RS
2.4
Varity_R
0.026
gMVP
0.42

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: rs141905334; hg19: chr7-102107850; API