Genetic Variant NIPA2:c.-58C>T (chr15-22851674-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_030922.7(NIPA2):c.-58C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,455,732 control chromosomes in the GnomAD database, including 590 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 45 hom., cov: 32)

Exomes 𝑓: 0.025 ( 545 hom. )

Consequence

NIPA2
NM_030922.7 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.568

Publications

3 publications found

Variant links:

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]

NIPA2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 15-22851674-C-T is Benign according to our data. Variant chr15-22851674-C-T is described in ClinVar as [Benign]. Clinvar id is 1248113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0193 (2935/152188) while in subpopulation NFE AF = 0.0247 (1680/68000). AF 95% confidence interval is 0.0237. There are 45 homozygotes in GnomAd4. There are 1518 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 45 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPA2	NM_030922.7 link	c.-58C>T		5_prime_UTR_variant	Exon 4 of 8	ENST00000337451.8	NP_112184.4	Q8N8Q9-1A0A024R372

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPA2	ENST00000337451.8 link	c.-58C>T		5_prime_UTR_variant	Exon 4 of 8	5	NM_030922.7	ENSP00000337618.3		Q8N8Q9-1

Frequencies

GnomAD3 genomes

AF:

0.0193

AC:

2935

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00432

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00850

Gnomad FIN

AF:

0.0734

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0247

Gnomad OTH

AF:

0.0110

GnomAD4 exome

AF:

0.0247

AC:

32134

AN:

1303544

Hom.:

545

Cov.:

AF XY:

0.0243

AC XY:

15803

AN XY:

650708

show subpopulations

African (AFR)

AF:

0.00303

AC:

AN:

28718

American (AMR)

AF:

0.00760

AC:

234

AN:

30778

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

431

AN:

22678

East Asian (EAS)

AF:

0.0000784

AC:

AN:

38272

South Asian (SAS)

AF:

0.00893

AC:

644

AN:

72098

European-Finnish (FIN)

AF:

0.0780

AC:

3991

AN:

51198

Middle Eastern (MID)

AF:

0.00744

AC:

AN:

5242

European-Non Finnish (NFE)

AF:

0.0255

AC:

25513

AN:

1000340

Other (OTH)

AF:

0.0220

AC:

1192

AN:

54220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1452

2903

4355

5806

7258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0193

AC:

2935

AN:

152188

Hom.:

Cov.:

AF XY:

0.0204

AC XY:

1518

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00431

AC:

179

AN:

41530

American (AMR)

AF:

0.0109

AC:

166

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00871

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0734

AC:

777

AN:

10588

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0247

AC:

1680

AN:

68000

Other (OTH)

AF:

0.0104

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

144

288

433

577

721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0203

Hom.:

Bravo

AF:

0.0145

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 13, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

0.57

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr15-22851674-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over