rs150688899

chrX-17725820-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001291867.2(NHS):c.1714C>T(p.Pro572Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0219 in 1,209,406 control chromosomes in the GnomAD database, including 888 homozygotes. There are 7,921 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (413 hom., 1753 hem., cov: 22)
  • Exomes 𝑓: 0.018 (475 hom. 6168 hem.)
• Consequence: NHS NM_001291867.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.86

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016627014).
• BP6: Variant X-17725820-C-T is Benign according to our data. Variant chrX-17725820-C-T is described in ClinVar as [Benign]. Clinvar id is 96632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-17725820-C-T is described in Lovd as [Benign]. Variant chrX-17725820-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHS	NM_001291867.2	c.1714C>T	p.Pro572Ser	missense_variant	7/9	ENST00000676302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHS	ENST00000676302.1	c.1714C>T	p.Pro572Ser	missense_variant	7/9		NM_001291867.2	P4

Frequencies

GnomAD3 genomes AF: 0.0614 AC: 6822 AN: 111142 Hom.: 413 Cov.: 22 AF XY: 0.0526 AC XY: 1754 AN XY: 33372

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.00294

Gnomad AMR AF: 0.0326

Gnomad ASJ AF: 0.00378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00803

Gnomad FIN AF: 0.00929

Gnomad MID AF: 0.0549

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.0694

GnomAD3 exomes AF: 0.0253 AC: 4619 AN: 182822 Hom.: 196 AF XY: 0.0212 AC XY: 1427 AN XY: 67406

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.00227

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00881

Gnomad FIN exome AF: 0.00889

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0228

GnomAD4 exome AF: 0.0179 AC: 19630 AN: 1098211 Hom.: 475 Cov.: 33 AF XY: 0.0170 AC XY: 6168 AN XY: 363565

Gnomad4 AFR exome AF: 0.190

Gnomad4 AMR exome AF: 0.0163

Gnomad4 ASJ exome AF: 0.00160

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00885

Gnomad4 FIN exome AF: 0.00901

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0257

GnomAD4 genome AF: 0.0613 AC: 6819 AN: 111195 Hom.: 413 Cov.: 22 AF XY: 0.0524 AC XY: 1753 AN XY: 33435

Gnomad4 AFR AF: 0.181

Gnomad4 AMR AF: 0.0325

Gnomad4 ASJ AF: 0.00378

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00806

Gnomad4 FIN AF: 0.00929

Gnomad4 NFE AF: 0.0146

Gnomad4 OTH AF: 0.0685

Alfa AF: 0.0187 Hom.: 876

Bravo AF: 0.0695

TwinsUK AF: 0.0175 AC: 65

ALSPAC AF: 0.0170 AC: 49

ESP6500AA AF: 0.191 AC: 734

ESP6500EA AF: 0.0149 AC: 100

ExAC AF: 0.0286 AC: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2019	This variant is associated with the following publications: (PMID: 27884173, 21559051) -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Nance-Horan syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	23
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	7.5e-8	P;P
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.7	D;D;.;.
REVEL	Benign	0.25
Sift	Uncertain	0.0090	D;D;.;.
Sift4G	Uncertain	0.024	D;D;D;D
Vest4		0.46
MPC		0.45
ClinPred		0.018	T
GERP RS		5.9
gMVP		0.67

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: rs150688899; hg19: chrX-17743940;