X-105895458-G-A

Variant names:

• chrX-105895458-G-A
• rs760958200
• NM_198465.4:c.515G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_198465.4(NRK):​c.515G>A​(p.Arg172Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000499 in 1,203,268 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: NRK NM_198465.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10719502).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

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.515G>A	p.Arg172Gln	missense	Exon 7 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.515G>A	p.Arg172Gln	missense	Exon 7 of 29	ENSP00000434830.1	Q7Z2Y5-1
	NRK	ENST00000882684.1		c.515G>A	p.Arg172Gln	missense	Exon 7 of 28	ENSP00000552743.1
	NRK	ENST00000882683.1		c.515G>A	p.Arg172Gln	missense	Exon 7 of 28	ENSP00000552742.1

Frequencies

GnomAD3 genomes AF: 0.00000897 AC: 1 AN: 111500 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000964

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 181339 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000458 AC: 5 AN: 1091768 Hom.: 0 Cov.: 28 AF XY: 0.00000559 AC XY: 2 AN XY: 357684

⚠️ 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: 26306

American (AMR) AF: 0.0000284 AC: 1 AN: 35185

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19335

East Asian (EAS) AF: 0.00 AC: 0 AN: 30162

South Asian (SAS) AF: 0.00 AC: 0 AN: 53958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4114

European-Non Finnish (NFE) AF: 0.00000478 AC: 4 AN: 836293

Other (OTH) AF: 0.00 AC: 0 AN: 45903

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0953088), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000897 AC: 1 AN: 111500 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33716

African (AFR) AF: 0.00 AC: 0 AN: 30734

American (AMR) AF: 0.0000964 AC: 1 AN: 10377

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.00 AC: 0 AN: 2634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6027

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53098

Other (OTH) AF: 0.00 AC: 0 AN: 1490

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000827 AC: 1

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	0.098
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.0
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.062
Sift	Benign	0.56	T
Sift4G	Benign	0.27	T
Polyphen		0.41	B
Vest4		0.17
MutPred		0.64		Loss of MoRF binding (P = 0.058)
MVP		0.44
ClinPred		0.42	T
GERP RS		3.6
Varity_R		0.067
gMVP		0.47
Mutation Taster		=87/13	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: rs760958200; hg19: chrX-105139451;