rs200598087

chrX-17692382-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001291867.2(NHS):c.766C>G(p.Leu256Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,208,245 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 75 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., 6 hem., cov: 22)
  • Exomes 𝑓: 0.00012 (0 hom. 69 hem.)
• Consequence: NHS NM_001291867.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.530

Genes affected

NHS (HGNC:7820): (NHS actin remodeling regulator) This gene encodes a protein containing four conserved nuclear localization signals. The encoded protein functions in eye, tooth, craniofacial and brain development, and it can regulate actin remodeling and cell morphology. Mutations in this gene have been shown to cause Nance-Horan syndrome, and also X-linked cataract-40. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0101546645).
• BP6: Variant X-17692382-C-G is Benign according to our data. Variant chrX-17692382-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129778.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAd at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHS	NM_001291867.2	c.766C>G	p.Leu256Val	missense_variant	3/9	ENST00000676302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHS	ENST00000676302.1	c.766C>G	p.Leu256Val	missense_variant	3/9		NM_001291867.2	P4

Frequencies

GnomAD3 genomes AF: 0.0000998 AC: 11 AN: 110246 Hom.: 0 Cov.: 22 AF XY: 0.000185 AC XY: 6 AN XY: 32458

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000759

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000196 AC: 36 AN: 183499 Hom.: 0 AF XY: 0.000294 AC XY: 20 AN XY: 67927

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00107

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000976

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 130 AN: 1097946 Hom.: 0 Cov.: 31 AF XY: 0.000190 AC XY: 69 AN XY: 363302

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00108

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00135

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000273

Gnomad4 OTH exome AF: 0.000195

GnomAD4 genome AF: 0.0000997 AC: 11 AN: 110299 Hom.: 0 Cov.: 22 AF XY: 0.000184 AC XY: 6 AN XY: 32521

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000759

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000133

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000109

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 16, 2014

The p.L256V variant (also known as c.766C>G), located in coding exon 3 of the NHS gene, results from a C to G substitution at nucleotide position 766. The leucine at codon 256 is replaced by valine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs200598087. This amino acid position is not conserved on species alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 04, 2017

- -

Nance-Horan syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.88
Dann	Benign	0.81
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.65	T;T;T;T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.63	N;N;.;.
REVEL	Benign	0.017
Sift	Benign	0.56	T;T;.;.
Sift4G	Benign	0.82	T;T;T;T
Vest4		0.088
MutPred		0.19		Gain of sheet (P = 0.0266);.;.;.;
MVP		0.15
MPC		0.35
ClinPred		0.011	T
GERP RS		2.8
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs200598087; hg19: chrX-17710502;