rs369785842

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_001291867.2(NHS):c.739C>T(p.Arg247Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,208,088 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 72 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., 5 hem., cov: 21)

Exomes 𝑓: 0.00020 ( 0 hom. 67 hem. )

Consequence

NHS
NM_001291867.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.71

Variant links:

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]

NHS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16267824).

BP6

Variant X-17692355-C-T is Benign according to our data. Variant chrX-17692355-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 435989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-17692355-C-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHS	NM_001291867.2 linkuse as main transcript	c.739C>T	p.Arg247Cys	missense_variant	3/9	ENST00000676302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHS	ENST00000676302.1 linkuse as main transcript	c.739C>T	p.Arg247Cys	missense_variant	3/9		NM_001291867.2	P4	Q6T4R5-1

Frequencies

GnomAD3 genomes

AF:

0.000155

AC:

AN:

109944

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

AN XY:

32220

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000323

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000927

AC:

AN:

183465

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

67893

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000195

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000204

AC:

224

AN:

1098092

Hom.:

Cov.:

AF XY:

0.000184

AC XY:

AN XY:

363450

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000253

Gnomad4 OTH exome

AF:

0.000217

GnomAD4 genome

AF:

0.000155

AC:

AN:

109996

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

AN XY:

32282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.000166

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 02, 2017

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2017

This alteration is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.43

Cadd

Uncertain

Dann

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.55

MetaRNN

Benign

0.16

T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.0

N;.;.;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.0

N;N;.;.

REVEL

Benign

0.11

Sift

Uncertain

0.0040

D;D;.;.

Sift4G

Benign

0.10

T;T;T;T

Vest4

0.37

MVP

0.32

MPC

1.2

ClinPred

0.20

GERP RS

5.5

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over