rs587780403

Variant summary

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

The NM_001291867.2(NHS):​c.2047G>A​(p.Val683Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000355 in 1,210,384 control chromosomes in the GnomAD database, including 1 homozygotes. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 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 0.000036 ( 0 hom., 0 hem., cov: 22)
Exomes 𝑓: 0.000036 ( 1 hom. 12 hem. )

Consequence

NHS
NM_001291867.2 missense

Scores

15

Clinical Significance

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

Conservation

PhyloP100: 1.00
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 -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.026078552).
BP6
Variant X-17726153-G-A is Benign according to our data. Variant chrX-17726153-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129772.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
BS2
High Hemizygotes in GnomAdExome4 at 12 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NHSNM_001291867.2 linkuse as main transcriptc.2047G>A p.Val683Met 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.2047G>A p.Val683Met missense_variant 7/9 NM_001291867.2 ENSP00000502262.1 Q6T4R5-1

Frequencies

GnomAD3 genomes
AF:
0.0000357
AC:
4
AN:
112081
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
34255
show subpopulations
Gnomad AFR
AF:
0.0000974
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000372
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000546
AC:
10
AN:
183299
Hom.:
0
AF XY:
0.0000295
AC XY:
2
AN XY:
67759
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:
0.000472
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000122
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000355
AC:
39
AN:
1098248
Hom.:
1
Cov.:
33
AF XY:
0.0000330
AC XY:
12
AN XY:
363602
show subpopulations
Gnomad4 AFR exome
AF:
0.0000758
Gnomad4 AMR exome
AF:
0.0000568
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000199
Gnomad4 SAS exome
AF:
0.000425
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000237
Gnomad4 OTH exome
AF:
0.0000868
GnomAD4 genome
AF:
0.0000357
AC:
4
AN:
112136
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
34320
show subpopulations
Gnomad4 AFR
AF:
0.0000971
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000373
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoDec 11, 2013- -
Nance-Horan syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 11, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.59
T
BayesDel_noAF
Benign
-0.77
CADD
Benign
13
DANN
Benign
0.49
DEOGEN2
Benign
0.012
.;.;T;T
FATHMM_MKL
Benign
0.49
N
LIST_S2
Benign
0.82
T;T;T;T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.026
T;T;T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.33
N;N;.;.
REVEL
Benign
0.058
Sift
Benign
0.65
T;T;.;.
Sift4G
Benign
0.11
T;T;T;T
Vest4
0.056
MVP
0.32
MPC
0.93
ClinPred
0.017
T
GERP RS
4.2
gMVP
0.25

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.

Other links and lift over

dbSNP: rs587780403; hg19: chrX-17744273; COSMIC: COSV66281724; COSMIC: COSV66281724; API