Genetic Variant NXNL2:p.Phe33Leu (chr9-88535533-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001161625.2(NXNL2):c.99C>G(p.Phe33Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,607,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

NXNL2
NM_001161625.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.677

Variant links:

Genes affected

NXNL2 (HGNC:30482): (nucleoredoxin like 2) Predicted to be involved in photoreceptor cell maintenance and sensory perception. Predicted to act upstream of or within sensory perception of smell and visual perception. [provided by Alliance of Genome Resources, Apr 2022]

NXNL2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NXNL2	NM_001161625.2 link	c.99C>G	p.Phe33Leu	missense_variant	Exon 1 of 2	ENST00000375854.8	NP_001155097.1	Q5VZ03-1
NXNL2	NM_145283.3 link	c.99C>G	p.Phe33Leu	missense_variant	Exon 1 of 3		NP_660326.2	Q5VZ03-3
NXNL2	XM_011518276.3 link	c.99C>G	p.Phe33Leu	missense_variant	Exon 1 of 2		XP_011516578.1
NXNL2	XM_005251727.4 link	c.99C>G	p.Phe33Leu	missense_variant	Exon 1 of 2		XP_005251784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NXNL2	ENST00000375854.8 link	c.99C>G	p.Phe33Leu	missense_variant	Exon 1 of 2	5	NM_001161625.2	ENSP00000365014.3	Q5VZ03-1
NXNL2	ENST00000375855.3 link	c.99C>G	p.Phe33Leu	missense_variant	Exon 1 of 3	1		ENSP00000365015.3	Q5VZ03-3
NXNL2	ENST00000649870.2 link	c.99C>G	p.Phe33Leu	missense_variant	Exon 2 of 3			ENSP00000508470.1	Q5VZ03-1
NXNL2	ENST00000478686.1 link	n.348C>G		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152108

Hom.:

Cov.:

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:

0.00116

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000989

AC:

AN:

232528

Hom.:

AF XY:

0.0000628

AC XY:

AN XY:

127482

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00131

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1455268

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

724024

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000556

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00117

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.0000665

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.99C>G (p.F33L) alteration is located in exon 1 (coding exon 1) of the NXNL2 gene. This alteration results from a C to G substitution at nucleotide position 99, causing the phenylalanine (F) at amino acid position 33 to be replaced by a leucine (L). 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

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

.;T;.

Eigen

Uncertain

0.37

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.85

D;T;T

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.88

D;D;D

MetaSVM

Uncertain

0.48

MutationAssessor

Pathogenic

3.6

.;H;H

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.8

.;D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0030

.;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0, 1.0

.;D;D

Vest4

0.79, 0.80

MutPred

0.87

Loss of catalytic residue at F33 (P = 0.0196);Loss of catalytic residue at F33 (P = 0.0196);Loss of catalytic residue at F33 (P = 0.0196);

MVP

0.75

MPC

1.9

ClinPred

0.64

GERP RS

2.1

Varity_R

0.74

gMVP

0.81

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over