rs398124607

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BP6BS2

The NM_001291867.2(NHS):c.302_337dupAGGCGGCGCCCGCAGCCGGCGAGGCGTCCTCGGCGG(p.Glu101_Ala112dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000467 in 1,055,580 control chromosomes in the GnomAD database, including 1 homozygotes. There are 173 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A113A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00050 ( 0 hom., 8 hem., cov: 23)

Exomes 𝑓: 0.00046 ( 1 hom. 165 hem. )

Consequence

NHS
NM_001291867.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 0.0890

Publications

0 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: Likely_benign. The variant received -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001291867.2

BP6

Variant X-17376055-C-CCGGAGGCGGCGCCCGCAGCCGGCGAGGCGTCCTCGG is Benign according to our data. Variant chrX-17376055-C-CCGGAGGCGGCGCCCGCAGCCGGCGAGGCGTCCTCGG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96638.

BS2

High AC in GnomAd4 at 56 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291867.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHS	NM_001291867.2	MANE Select	c.302_337dupAGGCGGCGCCCGCAGCCGGCGAGGCGTCCTCGGCGG	p.Glu101_Ala112dup	disruptive_inframe_insertion	Exon 1 of 9	NP_001278796.1
	NHS	NM_198270.4		c.302_337dupAGGCGGCGCCCGCAGCCGGCGAGGCGTCCTCGGCGG	p.Glu101_Ala112dup	disruptive_inframe_insertion	Exon 1 of 8	NP_938011.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHS	ENST00000676302.1	MANE Select	c.302_337dupAGGCGGCGCCCGCAGCCGGCGAGGCGTCCTCGGCGG	p.Glu101_Ala112dup	disruptive_inframe_insertion	Exon 1 of 9	ENSP00000502262.1
	NHS	ENST00000380060.7	TSL:1	c.302_337dupAGGCGGCGCCCGCAGCCGGCGAGGCGTCCTCGGCGG	p.Glu101_Ala112dup	disruptive_inframe_insertion	Exon 1 of 8	ENSP00000369400.3

Frequencies

GnomAD3 genomes

AF:

0.000504

AC:

AN:

111219

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00110

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000911

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000463

AC:

437

AN:

944326

Hom.:

Cov.:

AF XY:

0.000552

AC XY:

165

AN XY:

298806

show subpopulations

African (AFR)

AF:

0.000103

AC:

AN:

19454

American (AMR)

AF:

0.00

AC:

AN:

11940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14085

East Asian (EAS)

AF:

0.00

AC:

AN:

21508

South Asian (SAS)

AF:

0.000279

AC:

AN:

35841

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23744

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2518

European-Non Finnish (NFE)

AF:

0.000536

AC:

416

AN:

775691

Other (OTH)

AF:

0.000228

AC:

AN:

39545

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

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

100

<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:

0.000503

AC:

AN:

111254

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

AN XY:

33798

show subpopulations

African (AFR)

AF:

0.000162

AC:

AN:

30792

American (AMR)

AF:

0.00

AC:

AN:

10686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2631

East Asian (EAS)

AF:

0.00

AC:

AN:

3471

South Asian (SAS)

AF:

0.00111

AC:

AN:

2713

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5873

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.000911

AC:

AN:

52697

Other (OTH)

AF:

0.00

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

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

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Nov 03, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 01, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In-frame insertion of 12 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge

May 31, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nance-Horan syndrome

Uncertain:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.302_337dup, results in the insertion of 12 amino acid(s) of the NHS protein (p.Glu101_Ala112dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs398124607, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NHS-related conditions. ClinVar contains an entry for this variant (Variation ID: 96638). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Nance-Horan syndrome;C4049004:Cataract 40

Uncertain:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Nov 09, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.089

Mutation Taster

=80/20

polymorphism

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over