rs398124605

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001291867.2(NHS):c.211C>T(p.Pro71Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00557 in 1,074,258 control chromosomes in the GnomAD database, including 215 homozygotes. There are 1,592 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 119 hom., 863 hem., cov: 23)

Exomes 𝑓: 0.0029 ( 96 hom. 729 hem. )

Consequence

NHS
NM_001291867.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.642

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001693666).

BP6

Variant X-17375968-C-T is Benign according to our data. Variant chrX-17375968-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 96634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-17375968-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0962 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHS	NM_001291867.2 linkuse as main transcript	c.211C>T	p.Pro71Ser	missense_variant	1/9	ENST00000676302.1
NHS	NM_198270.4 linkuse as main transcript	c.211C>T	p.Pro71Ser	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHS	ENST00000676302.1 linkuse as main transcript	c.211C>T	p.Pro71Ser	missense_variant	1/9		NM_001291867.2	P4	Q6T4R5-1
NHS	ENST00000380060.7 linkuse as main transcript	c.211C>T	p.Pro71Ser	missense_variant	1/8	1		A2	Q6T4R5-2

Frequencies

GnomAD3 genomes

AF:

0.0287

AC:

3196

AN:

111221

Hom.:

119

Cov.:

AF XY:

0.0255

AC XY:

862

AN XY:

33783

show subpopulations

Gnomad AFR

AF:

0.0992

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00917

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00424

Gnomad NFE

AF:

0.000417

Gnomad OTH

AF:

0.0216

GnomAD3 exomes

AF:

0.00280

AC:

143

AN:

51037

Hom.:

AF XY:

0.00169

AC XY:

AN XY:

18883

show subpopulations

Gnomad AFR exome

AF:

0.112

Gnomad AMR exome

AF:

0.00460

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000107

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000326

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00290

AC:

2788

AN:

962991

Hom.:

Cov.:

AF XY:

0.00237

AC XY:

729

AN XY:

308143

show subpopulations

Gnomad4 AFR exome

AF:

0.102

Gnomad4 AMR exome

AF:

0.00654

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000392

Gnomad4 FIN exome

AF:

0.0000837

Gnomad4 NFE exome

AF:

0.000299

Gnomad4 OTH exome

AF:

0.00771

GnomAD4 genome

AF:

0.0288

AC:

3200

AN:

111267

Hom.:

119

Cov.:

AF XY:

0.0255

AC XY:

863

AN XY:

33839

show subpopulations

Gnomad4 AFR

AF:

0.0991

Gnomad4 AMR

AF:

0.00916

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000368

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000417

Gnomad4 OTH

AF:

0.0213

Alfa

AF:

0.0155

Hom.:

ExAC

AF:

0.00121

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 09, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2015	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2019

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.81

Cadd

Benign

6.1

Dann

Benign

0.97

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.39

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.50

REVEL

Benign

0.026

Sift

Benign

0.48

Sift4G

Benign

1.0

Vest4

0.20

MVP

0.13

MPC

0.35

ClinPred

0.0078

GERP RS

0.21

gMVP

0.085

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