8-142775623-T-C

Position:

• chr8-142775623-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_177477.4(LYNX1):​c.124A>G​(p.Met42Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,448,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 34)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: LYNX1 NM_177477.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.562

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]

LYNX1 (HGNC:):

ACMG classification

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=0.2156736).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LYNX1	NM_177477.4	c.124A>G	p.Met42Val	missense_variant	3/4	ENST00000652477.1	NP_803430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LYNX1	ENST00000652477.1	c.124A>G	p.Met42Val	missense_variant	3/4		NM_177477.4	ENSP00000498325.1
LYNX1-SLURP2	ENST00000615007.4	c.124A>G	p.Met42Val	missense_variant	3/5	1		ENSP00000479586.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1448810 Hom.: 0 Cov.: 34 AF XY: 0.00000417 AC XY: 3 AN XY: 719404

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2024

The c.124A>G (p.M42V) alteration is located in exon 3 (coding exon 2) of the LYNX1 gene. This alteration results from a A to G substitution at nucleotide position 124, causing the methionine (M) at amino acid position 42 to be replaced by a valine (V). 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	0.17
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.081	T;.;.;.;.;.;.
Eigen	Benign	-0.048
Eigen_PC	Benign	-0.0031
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.75	T;T;T;.;.;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.22	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;.;N;N;N;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.9	D;.;.;.;.;.;.
REVEL	Benign	0.063
Sift	Uncertain	0.019	D;.;.;.;.;.;.
Sift4G	Benign	0.10	T;D;T;T;T;T;T
Vest4		0.44
MutPred		0.34		Gain of catalytic residue at M42 (P = 0.1157);Gain of catalytic residue at M42 (P = 0.1157);Gain of catalytic residue at M42 (P = 0.1157);Gain of catalytic residue at M42 (P = 0.1157);Gain of catalytic residue at M42 (P = 0.1157);Gain of catalytic residue at M42 (P = 0.1157);Gain of catalytic residue at M42 (P = 0.1157);
MVP		0.31
ClinPred		0.16	T
GERP RS		2.3
Varity_R		0.14
gMVP		0.87

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

Other links and lift over

dbSNP: rs1198272056; hg19: chr8-143857041;