8-142775674-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_177477.4(LYNX1):​c.73G>A​(p.Val25Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000625 in 1,600,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

LYNX1
NM_177477.4 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.43
Variant links:
Genes affected
LYNX1 (HGNC:29604): (Ly6/neurotoxin 1) This gene encodes a GPI-anchored, cell membrane bound member of the Ly6/uPAR (LU) superfamily of proteins containing the unique three-finger LU domain. This protein interacts with nicotinic acetylcholine receptors (nAChRs), and is thought to function as a modulator of nAChR activity to prevent excessive excitation. Alternatively spliced transcript variants have been found for this gene. Read-through transcription between this gene and the neighboring downstream gene (SLURP2) generates naturally-occurring transcripts (LYNX1-SLURP2) that encode a fusion protein comprised of sequence sharing identity with each individual gene product. [provided by RefSeq, Sep 2017]
LYNX1-SLURP2 (HGNC:52291): (LYNX1-SLURP2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring LYNX1 and SLURP2 genes. The readthrough transcript encodes a fusion protein comprised of sequence sharing identity with each individual gene product. The significance of this read-through transcription and the function of the resulting protein product have not yet been determined. [provided by RefSeq, Sep 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.23834008).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LYNX1NM_177477.4 linkc.73G>A p.Val25Met missense_variant Exon 3 of 4 ENST00000652477.1 NP_803430.1 P0DP58-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LYNX1ENST00000652477.1 linkc.73G>A p.Val25Met missense_variant Exon 3 of 4 NM_177477.4 ENSP00000498325.1 P0DP58-1
LYNX1-SLURP2ENST00000615007.4 linkc.73G>A p.Val25Met missense_variant Exon 3 of 5 1 ENSP00000479586.1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152222
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
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:
0.0000268
AC:
6
AN:
223922
Hom.:
0
AF XY:
0.0000331
AC XY:
4
AN XY:
120716
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000593
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000499
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000677
AC:
98
AN:
1448296
Hom.:
0
Cov.:
34
AF XY:
0.0000612
AC XY:
44
AN XY:
719000
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000766
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000823
Gnomad4 OTH exome
AF:
0.0000668
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152222
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
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:
0.0000965
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 07, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.73G>A (p.V25M) alteration is located in exon 3 (coding exon 2) of the LYNX1 gene. This alteration results from a G to A substitution at nucleotide position 73, causing the valine (V) at amino acid position 25 to be replaced by a methionine (M). 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
Uncertain
0.48
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.34
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.19
T;.;.;.;.;.;.
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.85
T;T;T;.;.;T;T
M_CAP
Benign
0.045
D
MetaRNN
Benign
0.24
T;T;T;T;T;T;T
MetaSVM
Benign
-0.83
T
MutationAssessor
Benign
0.69
.;.;N;N;N;.;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-2.5
D;.;.;.;.;.;.
REVEL
Benign
0.24
Sift
Pathogenic
0.0
D;.;.;.;.;.;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D
Vest4
0.62
MutPred
0.27
Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP
0.21
ClinPred
0.55
D
GERP RS
3.9
Varity_R
0.13
gMVP
0.86

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: rs770292132; hg19: chr8-143857092; COSMIC: COSV59988971; API