rs3735887

Variant names:

• chr8-98193384-C-T
• rs3735887
• NM_001321635.2:c.1040-294G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 BA1

The NM_001321635.2(NIPAL2):​c.1040-294G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,612,268 control chromosomes in the GnomAD database, including 220,036 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.53 (21419 hom., cov: 32)
  • Exomes 𝑓: 0.52 (198617 hom.)
• Consequence: NIPAL2 NM_001321635.2 intron
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13
• Publications: 23 publications found

Genes affected

NIPAL2 (HGNC:25854): (NIPA like domain containing 2) 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]

NIPAL2-AS1 (HGNC:56271): (NIPAL2 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPAL2	NM_001321635.2	c.1040-294G>A		intron_variant	Intron 10 of 10	ENST00000430223.7	NP_001308564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPAL2	ENST00000430223.7	c.1040-294G>A		intron_variant	Intron 10 of 10	1	NM_001321635.2	ENSP00000407087.2
NIPAL2	ENST00000341166.3	c.1067+1G>A		splice_donor_variant, intron_variant	Intron 11 of 11	2		ENSP00000339256.3
NIPAL2	ENST00000520545.5	n.1059-294G>A		intron_variant	Intron 9 of 9	2

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80415 AN: 151894 Hom.: 21398 Cov.: 32

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.598

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.601

Gnomad SAS AF: 0.634

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.544

GnomAD2 exomes AF: 0.542 AC: 136366 AN: 251370 AF XY: 0.542

Gnomad AFR exome AF: 0.520

Gnomad AMR exome AF: 0.636

Gnomad ASJ exome AF: 0.559

Gnomad EAS exome AF: 0.593

Gnomad FIN exome AF: 0.510

Gnomad NFE exome AF: 0.496

Gnomad OTH exome AF: 0.540

GnomAD4 exome AF: 0.520 AC: 758742 AN: 1460256 Hom.: 198617 Cov.: 41 AF XY: 0.521 AC XY: 378176 AN XY: 726472

African (AFR) AF: 0.524 AC: 17537 AN: 33452

American (AMR) AF: 0.636 AC: 28449 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 14589 AN: 26132

East Asian (EAS) AF: 0.589 AC: 23387 AN: 39696

South Asian (SAS) AF: 0.605 AC: 52157 AN: 86200

European-Finnish (FIN) AF: 0.507 AC: 27092 AN: 53408

Middle Eastern (MID) AF: 0.531 AC: 3061 AN: 5764

European-Non Finnish (NFE) AF: 0.505 AC: 560508 AN: 1110548

Other (OTH) AF: 0.530 AC: 31962 AN: 60342

GnomAD4 genome AF: 0.529 AC: 80485 AN: 152012 Hom.: 21419 Cov.: 32 AF XY: 0.533 AC XY: 39616 AN XY: 74288

African (AFR) AF: 0.527 AC: 21841 AN: 41466

American (AMR) AF: 0.595 AC: 9087 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1971 AN: 3466

East Asian (EAS) AF: 0.601 AC: 3108 AN: 5168

South Asian (SAS) AF: 0.633 AC: 3046 AN: 4812

European-Finnish (FIN) AF: 0.516 AC: 5441 AN: 10552

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.502 AC: 34141 AN: 67952

Other (OTH) AF: 0.542 AC: 1146 AN: 2116

Alfa AF: 0.512 Hom.: 43416

Bravo AF: 0.532

TwinsUK AF: 0.491 AC: 1820

ALSPAC AF: 0.500 AC: 1928

ESP6500AA AF: 0.520 AC: 2289

ESP6500EA AF: 0.509 AC: 4379

ExAC AF: 0.536 AC: 65127

Asia WGS AF: 0.624 AC: 2172 AN: 3478

EpiCase AF: 0.504

EpiControl AF: 0.504

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	17
DANN	Benign	0.62
Eigen	Benign	0.089
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.00094	N
PhyloP100		1.1
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.77
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: rs3735887; hg19: chr8-99205612; COSMIC: COSV57841589; COSMIC: COSV57841589;