Genetic Variant NKAIN4:p.Asp92Asn (chr20-63247775-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152864.4(NKAIN4):c.274G>A(p.Asp92Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000276 in 1,450,654 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

NKAIN4
NM_152864.4 missense, splice_region

Scores

Splicing: ADA: 0.9761

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.81

Variant links:

Genes affected

NKAIN4 (HGNC:16191): (sodium/potassium transporting ATPase interacting 4) NKAIN4 is a member of a family of mammalian proteins (see NKAIN1; MIM 612871) with similarity to Drosophila Nkain and interacts with the beta subunit of Na,K-ATPase (ATP1B1; MIM 182330) (Gorokhova et al., 2007 [PubMed 17606467]).[supplied by OMIM, Jun 2009]

NKAIN4 links:

LOC124904950 (HGNC:):

LOC124904950 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKAIN4	NM_152864.4 link	c.274G>A	p.Asp92Asn	missense_variant, splice_region_variant	Exon 4 of 7	ENST00000370316.8	NP_690603.3	Q8IVV8B3KWY5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKAIN4	ENST00000370316.8 link	c.274G>A	p.Asp92Asn	missense_variant, splice_region_variant	Exon 4 of 7	1	NM_152864.4	ENSP00000359340.3		Q8IVV8

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000124

AC:

AN:

80932

Hom.:

AF XY:

0.00

AC XY:

AN XY:

39570

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000433

GnomAD4 exome

AF:

0.0000277

AC:

AN:

1298440

Hom.:

Cov.:

AF XY:

0.0000223

AC XY:

AN XY:

628378

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000321

Gnomad4 OTH exome

AF:

0.0000559

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000139

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.274G>A (p.D92N) alteration is located in exon 4 (coding exon 4) of the NKAIN4 gene. This alteration results from a G to A substitution at nucleotide position 274, causing the aspartic acid (D) at amino acid position 92 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.015

.;T;.;.

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.66

D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

.;M;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-4.2

D;D;D;D

REVEL

Benign

0.21

Sift

Benign

0.084

T;T;T;T

Sift4G

Benign

0.11

T;T;T;D

Polyphen

0.99

.;D;D;.

Vest4

0.36

MVP

0.39

MPC

0.047

ClinPred

0.99

GERP RS

3.6

Varity_R

0.24

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.75

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over