X-17727015-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_001291867.2(NHS):c.2909C>T(p.Thr970Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000529 in 1,210,145 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000062 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000052 ( 0 hom. 26 hem. )

Consequence

NHS
NM_001291867.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.91

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=0.30270985).

BP6

Variant X-17727015-C-T is Benign according to our data. Variant chrX-17727015-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 531901.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAdExome4 at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2 link	c.2909C>T	p.Thr970Met	missense_variant	Exon 7 of 9	ENST00000676302.1	NP_001278796.1	Q6T4R5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1 link	c.2909C>T	p.Thr970Met	missense_variant	Exon 7 of 9		NM_001291867.2	ENSP00000502262.1		Q6T4R5-1

Frequencies

GnomAD3 genomes

AF:

0.0000624

AC:

AN:

112154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34312

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000188

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:

0.0000939

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

183263

Hom.:

AF XY:

0.0000738

AC XY:

AN XY:

67753

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000367

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000519

AC:

AN:

1097991

Hom.:

Cov.:

AF XY:

0.0000716

AC XY:

AN XY:

363351

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.000499

Gnomad4 FIN exome

AF:

0.0000494

Gnomad4 NFE exome

AF:

0.0000273

Gnomad4 OTH exome

AF:

0.0000868

GnomAD4 genome

AF:

0.0000624

AC:

AN:

112154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000188

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000939

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Oct 06, 2014

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T949M variant (also known as c.2846C>T), located in coding exon 6 of the NHS gene, results from a C to T substitution at nucleotide position 2846. The threonine at codon 949 is replaced by methionine, an amino acid with some similar properties. This variant was previously reported in the SNPDatabase as rs373464879. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele was absent out of 2443 total male alleles studied. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Nance-Horan syndrome

Benign:1

Nov 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

.;.;T;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.30

T;T;T;T

MetaSVM

Uncertain

-0.16

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-3.6

D;D;.;.

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D;.;.

Sift4G

Uncertain

0.0060

D;D;D;D

Vest4

0.68

MVP

0.73

MPC

1.1

ClinPred

0.55

GERP RS

5.9

gMVP

0.66

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