9-88544491-G-A

Variant names:

• chr9-88544491-G-A
• NM_001161625.2:c.415G>A

Variant summary

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

The NM_001161625.2(NXNL2):​c.415G>A​(p.Ala139Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NXNL2 NM_001161625.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83

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]

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=0.12644485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NXNL2	NM_001161625.2	c.415G>A	p.Ala139Thr	missense_variant	Exon 2 of 2	ENST00000375854.8	NP_001155097.1
NXNL2	NM_145283.3	c.302+8755G>A		intron_variant	Intron 1 of 2		NP_660326.2
NXNL2	XM_011518276.3	c.302+8755G>A		intron_variant	Intron 1 of 1		XP_011516578.1
NXNL2	XM_005251727.4	c.302+8755G>A		intron_variant	Intron 1 of 1		XP_005251784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NXNL2	ENST00000375854.8	c.415G>A	p.Ala139Thr	missense_variant	Exon 2 of 2	5	NM_001161625.2	ENSP00000365014.3
NXNL2	ENST00000375855.3	c.302+8755G>A		intron_variant	Intron 1 of 2	1		ENSP00000365015.3
NXNL2	ENST00000649870.2	c.415G>A	p.Ala139Thr	missense_variant	Exon 3 of 3			ENSP00000508470.1
NXNL2	ENST00000478686.1	n.551+8755G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399058 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 689990

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.415G>A (p.A139T) alteration is located in exon 2 (coding exon 2) of the NXNL2 gene. This alteration results from a G to A substitution at nucleotide position 415, causing the alanine (A) at amino acid position 139 to be replaced by a threonine (T). 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	0.094
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.082
Sift	Benign	0.14	T
Sift4G	Benign	0.13	T
Polyphen		0.0010	B
Vest4		0.082
MutPred		0.41		Loss of catalytic residue at A139 (P = 0.0702);
MVP		0.30
MPC		0.68
ClinPred		0.41	T
GERP RS		1.5
Varity_R		0.030
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-91159406;