X-17692382-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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. 15/20 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.530

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Nance-Horan syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NHS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 129778.

BS2

High AC in GnomAd4 at 11 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2 link	c.766C>G	p.Leu256Val	missense_variant	Exon 3 of 9	ENST00000676302.1	NP_001278796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1 link	c.766C>G	p.Leu256Val	missense_variant	Exon 3 of 9		NM_001291867.2	ENSP00000502262.1

Frequencies

GnomAD3 genomes

AF:

0.0000998

AC:

AN:

110246

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000196

AC:

AN:

183499

AF XY:

0.000294

show subpopulations

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 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.:

Cov.:

AF XY:

0.000190

AC XY:

AN XY:

363302

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26396

American (AMR)

AF:

0.0000284

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00108

AC:

AN:

19381

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30204

South Asian (SAS)

AF:

0.00135

AC:

AN:

54144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0000273

AC:

AN:

841860

Other (OTH)

AF:

0.000195

AC:

AN:

46091

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000997

AC:

AN:

110299

Hom.:

Cov.:

AF XY:

0.000184

AC XY:

AN XY:

32521

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30292

American (AMR)

AF:

0.00

AC:

AN:

10352

Ashkenazi Jewish (ASJ)

AF:

0.000759

AC:

AN:

2636

East Asian (EAS)

AF:

0.00

AC:

AN:

3494

South Asian (SAS)

AF:

0.000831

AC:

AN:

2408

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5947

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

52761

Other (OTH)

AF:

0.00

AC:

AN:

1509

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Nov 16, 2014

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Aug 04, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nance-Horan syndrome

Benign:1

Jul 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.88

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.011

.;.;T;T

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.65

T;T;T;T

M_CAP

Benign

0.0092

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;.;.;.

PhyloP100

0.53

PrimateAI

Benign

0.42

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

GERP RS

2.8

gMVP

0.37

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over