15-22860655-A-G

Variant names:

• chr15-22860655-A-G
• rs748494134
• NM_030922.7:c.314A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030922.7(NIPA2):​c.314A>G​(p.Asn105Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000884 in 1,584,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000091 (0 hom.)
• Consequence: NIPA2 NM_030922.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14
• Publications: 0 publications found

Genes affected

NIPA2 (HGNC:17044): (NIPA magnesium transporter 2) This gene encodes a possible magnesium transporter. This gene is located adjacent to the imprinted domain in the Prader-Willi syndrome deletion region of chromosome 15. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 3, 7 and 21.[provided by RefSeq, May 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21586591).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030922.7. 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
	NIPA2	NM_030922.7	MANE Select	c.314A>G	p.Asn105Ser	missense	Exon 7 of 8	NP_112184.4
	NIPA2	NM_001008860.3		c.314A>G	p.Asn105Ser	missense	Exon 6 of 7	NP_001008860.1	Q8N8Q9-1
	NIPA2	NM_001008892.3		c.314A>G	p.Asn105Ser	missense	Exon 5 of 6	NP_001008892.1	Q8N8Q9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPA2	ENST00000337451.8	TSL:5 MANE Select	c.314A>G	p.Asn105Ser	missense	Exon 7 of 8	ENSP00000337618.3	Q8N8Q9-1
	NIPA2	ENST00000398013.7	TSL:1	c.314A>G	p.Asn105Ser	missense	Exon 5 of 6	ENSP00000381095.3	Q8N8Q9-1
	NIPA2	ENST00000359727.8	TSL:1	c.257A>G	p.Asn86Ser	missense	Exon 5 of 6	ENSP00000352762.4	Q8N8Q9-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000181 AC: 4 AN: 220458 AF XY: 0.0000251

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: 0.00

Gnomad OTH exome AF: 0.000387

GnomAD4 exome AF: 0.00000908 AC: 13 AN: 1432100 Hom.: 0 Cov.: 28 AF XY: 0.00000984 AC XY: 7 AN XY: 711640

African (AFR) AF: 0.0000626 AC: 2 AN: 31928

American (AMR) AF: 0.00 AC: 0 AN: 36710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25366

East Asian (EAS) AF: 0.00 AC: 0 AN: 38322

South Asian (SAS) AF: 0.0000632 AC: 5 AN: 79068

European-Finnish (FIN) AF: 0.0000564 AC: 3 AN: 53178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102612

Other (OTH) AF: 0.0000169 AC: 1 AN: 59222

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74326

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.22	T
PhyloP100		3.1
PROVEAN	Benign	-2.1	N
Sift	Benign	0.084	T
Sift4G	Benign	0.19	T
Vest4		0.22
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs748494134; hg19: chr15-23012413;