rs769860109

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_001291867.2(NHS):c.503A>G(p.Gln168Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000094 in 1,169,623 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.0000085 ( 0 hom. 4 hem. )

Consequence

NHS
NM_001291867.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.84

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27755043).

BS2

High AC in GnomAdExome4 at 9 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2 link	c.503A>G	p.Gln168Arg	missense_variant	Exon 1 of 9	ENST00000676302.1	NP_001278796.1	Q6T4R5-1
NHS	NM_198270.4 link	c.503A>G	p.Gln168Arg	missense_variant	Exon 1 of 8		NP_938011.1	Q6T4R5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1 link	c.503A>G	p.Gln168Arg	missense_variant	Exon 1 of 9		NM_001291867.2	ENSP00000502262.1		Q6T4R5-1
NHS	ENST00000380060.7 link	c.503A>G	p.Gln168Arg	missense_variant	Exon 1 of 8	1		ENSP00000369400.3		Q6T4R5-2

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000930

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000264

AC:

AN:

113556

AF XY:

0.0000276

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000135

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000851

AC:

AN:

1057687

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

343447

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25742

American (AMR)

AF:

0.000128

AC:

AN:

31329

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18843

East Asian (EAS)

AF:

0.00

AC:

AN:

28528

South Asian (SAS)

AF:

0.00

AC:

AN:

50763

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4013

European-Non Finnish (NFE)

AF:

0.00000605

AC:

AN:

827121

Other (OTH)

AF:

0.00

AC:

AN:

44848

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

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:

0.0000179

AC:

AN:

111936

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34182

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30898

American (AMR)

AF:

0.0000930

AC:

AN:

10756

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3492

South Asian (SAS)

AF:

0.00

AC:

AN:

2707

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6077

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52943

Other (OTH)

AF:

0.00

AC:

AN:

1505

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000918

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 25, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nance-Horan syndrome

Uncertain:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 168 of the NHS protein (p.Gln168Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 435994). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.94

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.65

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.28

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

7.8

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.45

REVEL

Benign

0.20

Sift

Benign

0.18

Sift4G

Benign

0.84

Vest4

0.43

MutPred

0.45

Gain of MoRF binding (P = 0.0432);

MVP

0.45

MPC

0.44

ClinPred

0.28

GERP RS

3.9

gMVP

0.66

Mutation Taster

=94/6

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over