chrX-17728157-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001291867.2(NHS):​c.4051G>A​(p.Asp1351Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,209,941 control chromosomes in the GnomAD database, including 2 homozygotes. There are 40 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 0.00020 ( 0 hom., 9 hem., cov: 23)
Exomes 𝑓: 0.00012 ( 2 hom. 31 hem. )

Consequence

NHS
NM_001291867.2 missense

Scores

2
13

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.44
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.009212434).
BP6
Variant X-17728157-G-A is Benign according to our data. Variant chrX-17728157-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 211599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-17728157-G-A is described in Lovd as [Likely_benign].
BS2
High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NHSNM_001291867.2 linkuse as main transcriptc.4051G>A p.Asp1351Asn missense_variant 7/9 ENST00000676302.1 NP_001278796.1 Q6T4R5-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NHSENST00000676302.1 linkuse as main transcriptc.4051G>A p.Asp1351Asn missense_variant 7/9 NM_001291867.2 ENSP00000502262.1 Q6T4R5-1

Frequencies

GnomAD3 genomes
AF:
0.000197
AC:
22
AN:
111796
Hom.:
0
Cov.:
23
AF XY:
0.000265
AC XY:
9
AN XY:
33974
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00133
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:
0.000113
Gnomad OTH
AF:
0.00133
GnomAD3 exomes
AF:
0.000496
AC:
91
AN:
183355
Hom.:
1
AF XY:
0.000295
AC XY:
20
AN XY:
67805
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00248
Gnomad ASJ exome
AF:
0.000134
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000978
Gnomad OTH exome
AF:
0.00309
GnomAD4 exome
AF:
0.000125
AC:
137
AN:
1098145
Hom.:
2
Cov.:
32
AF XY:
0.0000853
AC XY:
31
AN XY:
363499
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00253
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000185
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000404
Gnomad4 OTH exome
AF:
0.000239
GnomAD4 genome
AF:
0.000197
AC:
22
AN:
111796
Hom.:
0
Cov.:
23
AF XY:
0.000265
AC XY:
9
AN XY:
33974
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00133
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000113
Gnomad4 OTH
AF:
0.00133
Alfa
AF:
0.000211
Hom.:
2
Bravo
AF:
0.000604
ESP6500AA
AF:
0.000261
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000519
AC:
63
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJul 17, 2015- -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsOct 28, 2016This 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2024- -
NHS-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 26, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.73
T
BayesDel_noAF
Benign
-0.82
CADD
Benign
11
DANN
Uncertain
1.0
DEOGEN2
Benign
0.024
.;.;T;T
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.77
T;T;T;T
M_CAP
Benign
0.0082
T
MetaRNN
Benign
0.0092
T;T;T;T
MetaSVM
Benign
-0.89
T
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-1.1
N;N;.;.
REVEL
Benign
0.16
Sift
Benign
0.16
T;T;.;.
Sift4G
Benign
0.17
T;T;T;T
Vest4
0.13
MVP
0.25
MPC
0.36
ClinPred
0.062
T
GERP RS
4.0
gMVP
0.21

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs148418212; hg19: chrX-17746277; API