rs145005596

Positions:

chrX-17727480-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001291867.2(NHS):c.3374C>T(p.Ser1125Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000515 in 1,209,121 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 190 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/17 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 0.00050 ( 0 hom., 8 hem., cov: 23)

Exomes 𝑓: 0.00052 ( 0 hom. 182 hem. )

Consequence

NHS
NM_001291867.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.29

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015018314).

BP6

Variant X-17727480-C-T is Benign according to our data. Variant chrX-17727480-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198289.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}. Variant chrX-17727480-C-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHS	NM_001291867.2 linkuse as main transcript	c.3374C>T	p.Ser1125Leu	missense_variant	7/9	ENST00000676302.1	NP_001278796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1 linkuse as main transcript	c.3374C>T	p.Ser1125Leu	missense_variant	7/9		NM_001291867.2	ENSP00000502262	P4	Q6T4R5-1

Frequencies

GnomAD3 genomes

AF:

0.000501

AC:

AN:

111731

Hom.:

Cov.:

AF XY:

0.000236

AC XY:

AN XY:

33919

show subpopulations

Gnomad AFR

AF:

0.00121

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:

0.000357

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000316

AC:

AN:

183271

Hom.:

AF XY:

0.000340

AC XY:

AN XY:

67743

show subpopulations

Gnomad AFR exome

AF:

0.00144

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000440

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000517

AC:

567

AN:

1097336

Hom.:

Cov.:

AF XY:

0.000502

AC XY:

182

AN XY:

362702

show subpopulations

Gnomad4 AFR exome

AF:

0.00140

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000370

Gnomad4 FIN exome

AF:

0.0000494

Gnomad4 NFE exome

AF:

0.000613

Gnomad4 OTH exome

AF:

0.000217

GnomAD4 genome

AF:

0.000501

AC:

AN:

111785

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

AN XY:

33983

show subpopulations

Gnomad4 AFR

AF:

0.00120

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:

0.000357

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000524

Hom.:

Bravo

AF:

0.000703

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 28, 2015	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2017

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.066

.;.;T;T

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Benign

0.044

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.5

D;N;.;.

REVEL

Benign

0.097

Sift

Benign

0.10

T;T;.;.

Sift4G

Benign

0.091

T;T;T;T

Vest4

0.086

MVP

0.33

MPC

0.48

ClinPred

0.044

GERP RS

5.9

gMVP

0.56

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