X-105880232-G-A

Variant names:

• chrX-105880232-G-A
• NM_198465.4:c.157G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198465.4(NRK):​c.157G>A​(p.Val53Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000103 in 969,363 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000010 (0 hom. 0 hem.)
• Consequence: NRK NM_198465.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71
• Publications: 0 publications found

Genes affected

NRK (HGNC:25391): (Nik related kinase) The mouse ortholog of this gene encodes a protein kinase required for JNK activation. The encoded protein may be involved in the induction of actin polymerization in late embryogenesis.[provided by RefSeq, Jun 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16984057).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198465.4. 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
	NRK	NM_198465.4	MANE Select	c.157G>A	p.Val53Ile	missense	Exon 3 of 29	NP_940867.2	Q7Z2Y5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRK	ENST00000243300.14	TSL:1 MANE Select	c.157G>A	p.Val53Ile	missense	Exon 3 of 29	ENSP00000434830.1	Q7Z2Y5-1
	NRK	ENST00000536164.5	TSL:1	c.157G>A	p.Val53Ile	missense	Exon 3 of 7	ENSP00000438785.1	Q7Z2Y5-3
	NRK	ENST00000882684.1		c.157G>A	p.Val53Ile	missense	Exon 3 of 28	ENSP00000552743.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000103 AC: 1 AN: 969363 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 283211

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22907

American (AMR) AF: 0.00 AC: 0 AN: 26741

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17422

East Asian (EAS) AF: 0.00 AC: 0 AN: 26012

South Asian (SAS) AF: 0.00 AC: 0 AN: 40204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36551

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3811

European-Non Finnish (NFE) AF: 0.00000132 AC: 1 AN: 754851

Other (OTH) AF: 0.00 AC: 0 AN: 40864

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

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	Benign	0.093
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	16
DANN	Benign	0.68
DEOGEN2	Benign	0.080	T
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.27	N
PhyloP100		2.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.054
Sift	Benign	0.99	T
Sift4G	Benign	1.0	T
Polyphen		0.074	B
Vest4		0.15
MutPred		0.64		Loss of MoRF binding (P = 0.1316)
MVP		0.42
ClinPred		0.23	T
GERP RS		3.7
Varity_R		0.058
gMVP		0.18
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chrX-105124225;