chr20-63247733-A-T

Variant names:

• chr20-63247733-A-T
• NM_152864.4:c.316T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_152864.4(NKAIN4):​c.316T>A​(p.Trp106Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NKAIN4 NM_152864.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.02
• Publications: 0 publications found

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]

LOC124904950 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152864.4. 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
	NKAIN4	NM_152864.4	MANE Select	c.316T>A	p.Trp106Arg	missense	Exon 4 of 7	NP_690603.3
	NKAIN4	NM_001363747.1		c.130T>A	p.Trp44Arg	missense	Exon 4 of 7	NP_001350676.1	A6NNM2
	NKAIN4	NM_001363718.1		c.130T>A	p.Trp44Arg	missense	Exon 4 of 6	NP_001350647.1	J3JS66

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKAIN4	ENST00000370316.8	TSL:1 MANE Select	c.316T>A	p.Trp106Arg	missense	Exon 4 of 7	ENSP00000359340.3	Q8IVV8
	NKAIN4	ENST00000370317.3	TSL:5	c.106T>A	p.Trp36Arg	missense	Exon 2 of 6	ENSP00000359341.3	J9JIE8
	NKAIN4	ENST00000370307.6	TSL:5	c.130T>A	p.Trp44Arg	missense	Exon 4 of 7	ENSP00000359330.2	A6NNM2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.46e-7 AC: 1 AN: 1340718 Hom.: 0 Cov.: 34 AF XY: 0.00000153 AC XY: 1 AN XY: 654550

African (AFR) AF: 0.00 AC: 0 AN: 29818

American (AMR) AF: 0.00 AC: 0 AN: 27718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21892

East Asian (EAS) AF: 0.0000286 AC: 1 AN: 35010

South Asian (SAS) AF: 0.00 AC: 0 AN: 69688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5356

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1049494

Other (OTH) AF: 0.00 AC: 0 AN: 55392

GnomAD4 genome Cov.: 34

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	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-14	D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.91		Gain of disorder (P = 0.0016)
MVP		0.44
MPC		0.040
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.85
gMVP		0.74
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.41		Position offset: -2

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

Other links and lift over

hg19: chr20-61879085;