1-24440173-A-G

Variant names:

• chr1-24440173-A-G
• rs766406791
• NM_020448.5:c.95A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020448.5(NIPAL3):​c.95A>G​(p.Glu32Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,433,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E32A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NIPAL3 NM_020448.5 missense, splice_region
• Scores: Splicing: ADA: 0.4451
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.43
• Publications: 0 publications found

Genes affected

NIPAL3 (HGNC:25233): (NIPA like domain containing 3) Predicted to enable magnesium ion transmembrane transporter activity. Predicted to be involved in magnesium ion transport. Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020448.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPAL3	NM_020448.5	MANE Select	c.95A>G	p.Glu32Gly	missense splice_region	Exon 3 of 12	NP_065181.1	Q6P499-1
	NIPAL3	NM_001322854.2		c.95A>G	p.Glu32Gly	missense splice_region	Exon 3 of 12	NP_001309783.1	Q6P499-1
	NIPAL3	NM_001322855.2		c.95A>G	p.Glu32Gly	missense splice_region	Exon 4 of 13	NP_001309784.1	Q6P499-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPAL3	ENST00000374399.9	TSL:1 MANE Select	c.95A>G	p.Glu32Gly	missense splice_region	Exon 3 of 12	ENSP00000363520.4	Q6P499-1
	NIPAL3	ENST00000003912.9	TSL:1	c.-152A>G		splice_region	Exon 4 of 13	ENSP00000003912.3
	NIPAL3	ENST00000358028.8	TSL:1	c.95A>G	p.Glu32Gly	missense splice_region	Exon 3 of 8	ENSP00000350722.4	Q6P499-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000876 AC: 2 AN: 228222 AF XY: 0.00000809

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000191

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1433358 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 712420

African (AFR) AF: 0.00 AC: 0 AN: 32464

American (AMR) AF: 0.00 AC: 0 AN: 40344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24772

East Asian (EAS) AF: 0.00 AC: 0 AN: 38112

South Asian (SAS) AF: 0.00 AC: 0 AN: 81906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5648

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098608

Other (OTH) AF: 0.00 AC: 0 AN: 58978

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.2	N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.011	D
Polyphen		0.98	D
Vest4		0.79
MutPred		0.66		Loss of stability (P = 0.0439)
MVP		0.85
MPC		0.87
ClinPred		0.88	D
GERP RS		5.0
Varity_R		0.47
gMVP		0.54
Mutation Taster		=211/89	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.45
dbscSNV1_RF	Benign	0.58
Splicevardb		1.0
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

Other links and lift over

dbSNP: rs766406791; hg19: chr1-24766663;