rs41304731

chrX-17728035-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001291867.2(NHS):c.3929G>T(p.Gly1310Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,209,897 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 536 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., 32 hem., cov: 23)
  • Exomes 𝑓: 0.0014 (0 hom. 504 hem.)
• Consequence: NHS NM_001291867.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.689

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011122316).
• BP6: Variant X-17728035-G-T is Benign according to our data. Variant chrX-17728035-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 96640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-17728035-G-T is described in Lovd as [Benign]. Variant chrX-17728035-G-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 32 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHS	NM_001291867.2	c.3929G>T	p.Gly1310Val	missense_variant	7/9	ENST00000676302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHS	ENST00000676302.1	c.3929G>T	p.Gly1310Val	missense_variant	7/9		NM_001291867.2	P4

Frequencies

GnomAD3 genomes AF: 0.000752 AC: 84 AN: 111672 Hom.: 0 Cov.: 23 AF XY: 0.000945 AC XY: 32 AN XY: 33848

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00152

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.00120

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.000661 AC: 121 AN: 183187 Hom.: 0 AF XY: 0.000665 AC XY: 45 AN XY: 67667

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000693

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000125

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.00137 AC: 1501 AN: 1098172 Hom.: 0 Cov.: 32 AF XY: 0.00139 AC XY: 504 AN XY: 363528

Gnomad4 AFR exome AF: 0.000189

Gnomad4 AMR exome AF: 0.000596

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000554

Gnomad4 FIN exome AF: 0.000222

Gnomad4 NFE exome AF: 0.00169

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.000752 AC: 84 AN: 111725 Hom.: 0 Cov.: 23 AF XY: 0.000944 AC XY: 32 AN XY: 33911

Gnomad4 AFR AF: 0.0000326

Gnomad4 AMR AF: 0.00152

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00120

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.000981 Hom.: 40

Bravo AF: 0.000669

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00138 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00119 AC: 8

ExAC AF: 0.000601 AC: 73

EpiCase AF: 0.000545

EpiControl AF: 0.00166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 09, 2018	- -

Nance-Horan syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

NHS-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2021

This 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	-0.83	T
BayesDel_noAF	Benign	-1.0
Cadd	Benign	1.6
Dann	Benign	0.095
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.070	N;N;.;.
REVEL	Benign	0.018
Sift	Benign	0.31	T;T;.;.
Sift4G	Benign	0.49	T;T;T;T
Vest4		0.035
MVP		0.068
MPC		0.43
ClinPred		0.0014	T
GERP RS		-5.1
gMVP		0.19

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

Other links and lift over

dbSNP: rs41304731; hg19: chrX-17746155;