chr1-24419566-G-A

Variant names:

• chr1-24419566-G-A
• rs148391167
• NM_020448.5:c.19G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_020448.5(NIPAL3):​c.19G>A​(p.Ala7Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,613,788 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (14 hom.)
• Consequence: NIPAL3 NM_020448.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.395
• Publications: 6 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029473603).
• BP6: Variant 1-24419566-G-A is Benign according to our data. Variant chr1-24419566-G-A is described in ClinVar as Benign. ClinVar VariationId is 3033822.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.19G>A	p.Ala7Thr	missense	Exon 2 of 12	NP_065181.1	Q6P499-1
	NIPAL3	NM_001322854.2		c.19G>A	p.Ala7Thr	missense	Exon 2 of 12	NP_001309783.1	Q6P499-1
	NIPAL3	NM_001322855.2		c.19G>A	p.Ala7Thr	missense	Exon 3 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.19G>A	p.Ala7Thr	missense	Exon 2 of 12	ENSP00000363520.4	Q6P499-1
	NIPAL3	ENST00000358028.8	TSL:1	c.19G>A	p.Ala7Thr	missense	Exon 2 of 8	ENSP00000350722.4	Q6P499-3
	NIPAL3	ENST00000003912.9	TSL:1	c.-338G>A		5_prime_UTR	Exon 2 of 13	ENSP00000003912.3

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 377 AN: 152234 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00363

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00278 AC: 690 AN: 248008 AF XY: 0.00271

Gnomad AFR exome AF: 0.000500

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0103

Gnomad FIN exome AF: 0.000466

Gnomad NFE exome AF: 0.00381

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00355 AC: 5186 AN: 1461436 Hom.: 14 Cov.: 30 AF XY: 0.00356 AC XY: 2591 AN XY: 727008

African (AFR) AF: 0.000418 AC: 14 AN: 33462

American (AMR) AF: 0.000447 AC: 20 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26124

East Asian (EAS) AF: 0.0153 AC: 607 AN: 39680

South Asian (SAS) AF: 0.00102 AC: 88 AN: 86142

European-Finnish (FIN) AF: 0.000824 AC: 44 AN: 53380

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00378 AC: 4205 AN: 1111826

Other (OTH) AF: 0.00277 AC: 167 AN: 60362

GnomAD4 genome AF: 0.00247 AC: 376 AN: 152352 Hom.: 3 Cov.: 32 AF XY: 0.00231 AC XY: 172 AN XY: 74502

African (AFR) AF: 0.000986 AC: 41 AN: 41582

American (AMR) AF: 0.000327 AC: 5 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.0110 AC: 57 AN: 5184

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4830

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00362 AC: 246 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00303 Hom.: 2

Bravo AF: 0.00227

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00268 AC: 326

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00380

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	NIPAL3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	7.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.0029	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.40
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.081
Sift	Benign	0.062	T
Sift4G	Benign	0.21	T
Polyphen		0.027	B
Vest4		0.27
MVP		0.52
MPC		0.21
ClinPred		0.0012	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.64
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs148391167; hg19: chr1-24746056; COSMIC: COSV99042855; COSMIC: COSV99042855;