X-17728124-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001291867.2(NHS):c.4018T>C(p.Phe1340Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0892 in 1,209,376 control chromosomes in the GnomAD database, including 20,115 homozygotes. There are 31,843 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 8322 hom., 8960 hem., cov: 22)

Exomes 𝑓: 0.069 ( 11793 hom. 22883 hem. )

Consequence

NHS
NM_001291867.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.101

Publications

20 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:

ENSG00000309710 (HGNC:):

ENSG00000309710 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.097197E-7).

BP6

Variant X-17728124-T-C is Benign according to our data. Variant chrX-17728124-T-C is described in ClinVar as Benign. ClinVar VariationId is 129776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2 link	c.4018T>C	p.Phe1340Leu	missense_variant	Exon 7 of 9	ENST00000676302.1	NP_001278796.1	Q6T4R5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1 link	c.4018T>C	p.Phe1340Leu	missense_variant	Exon 7 of 9		NM_001291867.2	ENSP00000502262.1		Q6T4R5-1

Frequencies

GnomAD3 genomes

AF:

0.286

AC:

31762

AN:

111144

Hom.:

8315

Cov.:

show subpopulations

Gnomad AFR

AF:

0.829

Gnomad AMI

AF:

0.00292

Gnomad AMR

AF:

0.289

Gnomad ASJ

AF:

0.0565

Gnomad EAS

AF:

0.428

Gnomad SAS

AF:

0.0578

Gnomad FIN

AF:

0.0200

Gnomad MID

AF:

0.173

Gnomad NFE

AF:

0.0229

Gnomad OTH

AF:

0.291

GnomAD2 exomes

AF:

0.169

AC:

30921

AN:

183226

AF XY:

0.132

show subpopulations

Gnomad AFR exome

AF:

0.843

Gnomad AMR exome

AF:

0.347

Gnomad ASJ exome

AF:

0.0529

Gnomad EAS exome

AF:

0.435

Gnomad FIN exome

AF:

0.0197

Gnomad NFE exome

AF:

0.0253

Gnomad OTH exome

AF:

0.125

GnomAD4 exome

AF:

0.0692

AC:

76037

AN:

1098178

Hom.:

11793

Cov.:

AF XY:

0.0629

AC XY:

22883

AN XY:

363536

show subpopulations

African (AFR)

AF:

0.853

AC:

22510

AN:

26400

American (AMR)

AF:

0.343

AC:

12058

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.0545

AC:

1057

AN:

19386

East Asian (EAS)

AF:

0.450

AC:

13599

AN:

30205

South Asian (SAS)

AF:

0.0496

AC:

2686

AN:

54147

European-Finnish (FIN)

AF:

0.0192

AC:

780

AN:

40530

Middle Eastern (MID)

AF:

0.161

AC:

665

AN:

4137

European-Non Finnish (NFE)

AF:

0.0201

AC:

16943

AN:

842075

Other (OTH)

AF:

0.125

AC:

5739

AN:

46094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

2306

4613

6919

9226

11532

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1224

2448

3672

4896

6120

<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:

0.286

AC:

31835

AN:

111198

Hom.:

8322

Cov.:

AF XY:

0.268

AC XY:

8960

AN XY:

33422

show subpopulations

African (AFR)

AF:

0.829

AC:

25182

AN:

30363

American (AMR)

AF:

0.290

AC:

3042

AN:

10487

Ashkenazi Jewish (ASJ)

AF:

0.0565

AC:

149

AN:

2639

East Asian (EAS)

AF:

0.427

AC:

1476

AN:

3459

South Asian (SAS)

AF:

0.0583

AC:

156

AN:

2674

European-Finnish (FIN)

AF:

0.0200

AC:

121

AN:

6038

Middle Eastern (MID)

AF:

0.171

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0229

AC:

1219

AN:

53119

Other (OTH)

AF:

0.297

AC:

451

AN:

1519

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

311

622

932

1243

1554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.141

Hom.:

16058

Bravo

AF:

0.339

TwinsUK

AF:

0.0267

AC:

ALSPAC

AF:

0.0239

AC:

ESP6500AA

AF:

0.815

AC:

3124

ESP6500EA

AF:

0.0268

AC:

180

ExAC

AF:

0.161

AC:

19584

EpiCase

AF:

0.0305

EpiControl

AF:

0.0309

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jan 31, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 02, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases

Benign:1

Jun 22, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 03, 2025

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

0.11

BayesDel_addAF

Benign

-0.97

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.58

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.0017

.;.;T;T

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.16

T;T;T;T

MetaRNN

Benign

6.1e-7

T;T;T;T

MetaSVM

Benign

-0.99

PhyloP100

0.10

PrimateAI

Benign

0.29

PROVEAN

Benign

0.57

N;N;.;.

REVEL

Benign

0.034

Sift

Benign

1.0

T;T;.;.

Sift4G

Benign

0.66

T;T;T;T

Vest4

0.018

MPC

0.40

ClinPred

0.000012

GERP RS

0.69

gMVP

0.13

Mutation Taster

=100/0

polymorphism (auto)

(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