X-17375909-C-T

Position:

chrX-17375909-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001291867.2(NHS):c.152C>T(p.Ala51Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000895 in 1,094,804 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 34 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 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 0.000045 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000095 ( 0 hom. 32 hem. )

Consequence

NHS
NM_001291867.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.309

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08774322).

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHS	NM_001291867.2 linkuse as main transcript	c.152C>T	p.Ala51Val	missense_variant	1/9	ENST00000676302.1	NP_001278796.1
NHS	NM_198270.4 linkuse as main transcript	c.152C>T	p.Ala51Val	missense_variant	1/8		NP_938011.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1 linkuse as main transcript	c.152C>T	p.Ala51Val	missense_variant	1/9		NM_001291867.2	ENSP00000502262	P4	Q6T4R5-1
NHS	ENST00000380060.7 linkuse as main transcript	c.152C>T	p.Ala51Val	missense_variant	1/8	1		ENSP00000369400	A2	Q6T4R5-2

Frequencies

GnomAD3 genomes

AF:

0.0000448

AC:

AN:

111563

Hom.:

Cov.:

AF XY:

0.0000588

AC XY:

AN XY:

34013

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:

0.0000757

Gnomad OTH

AF:

0.000667

GnomAD3 exomes

AF:

0.000154

AC:

AN:

45459

Hom.:

AF XY:

0.00

AC XY:

AN XY:

12783

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000399

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:

0.0000566

Gnomad OTH exome

AF:

0.00141

GnomAD4 exome

AF:

0.0000946

AC:

AN:

983241

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

315437

show subpopulations

Gnomad4 AFR exome

AF:

0.000146

Gnomad4 AMR exome

AF:

0.000567

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000471

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000743

Gnomad4 OTH exome

AF:

0.000363

GnomAD4 genome

AF:

0.0000448

AC:

AN:

111563

Hom.:

Cov.:

AF XY:

0.0000588

AC XY:

AN XY:

34013

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:

0.0000757

Gnomad4 OTH

AF:

0.000667

Alfa

AF:

0.000137

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000760

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2016	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nance-Horan syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 51 of the NHS protein (p.Ala51Val). This variant is present in population databases (rs727504039, gnomAD 0.04%). 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: 167351). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2022

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Uncertain

1.0

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.37

M_CAP

Benign

0.062

MetaRNN

Benign

0.088

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.23

REVEL

Benign

0.016

Sift

Benign

0.10

Sift4G

Uncertain

0.031

Vest4

0.097

MutPred

0.21

Gain of sheet (P = 0.0221);

MVP

0.42

MPC

0.34

ClinPred

0.033

GERP RS

1.4

gMVP

0.055

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

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