X-17375806-C-T

Variant names:

• chrX-17375806-C-T
• rs794726963
• NM_001291867.2:c.49C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001291867.2(NHS):​c.49C>T​(p.Arg17Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,150,809 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000012 (0 hom. 6 hem.)
• Consequence: NHS NM_001291867.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.262
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Nance-Horan syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24517104).
• BS2: High AC in GnomAdExome4 at 12 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2	c.49C>T	p.Arg17Trp	missense_variant	Exon 1 of 9	ENST00000676302.1	NP_001278796.1
NHS	NM_198270.4	c.49C>T	p.Arg17Trp	missense_variant	Exon 1 of 8		NP_938011.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1	c.49C>T	p.Arg17Trp	missense_variant	Exon 1 of 9		NM_001291867.2	ENSP00000502262.1
NHS	ENST00000380060.7	c.49C>T	p.Arg17Trp	missense_variant	Exon 1 of 8	1		ENSP00000369400.3

Frequencies

GnomAD3 genomes AF: 0.00000889 AC: 1 AN: 112536 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 12 AN: 1038273 Hom.: 0 Cov.: 31 AF XY: 0.0000177 AC XY: 6 AN XY: 339291

African (AFR) AF: 0.00 AC: 0 AN: 24695

American (AMR) AF: 0.00 AC: 0 AN: 27770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18519

East Asian (EAS) AF: 0.00 AC: 0 AN: 26992

South Asian (SAS) AF: 0.00 AC: 0 AN: 49620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25583

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2839

European-Non Finnish (NFE) AF: 0.0000134 AC: 11 AN: 818195

Other (OTH) AF: 0.0000227 AC: 1 AN: 44060

GnomAD4 genome AF: 0.00000889 AC: 1 AN: 112536 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34736

African (AFR) AF: 0.00 AC: 0 AN: 31086

American (AMR) AF: 0.00 AC: 0 AN: 10809

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3523

South Asian (SAS) AF: 0.00 AC: 0 AN: 2778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53093

Other (OTH) AF: 0.00 AC: 0 AN: 1520

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.49C>T (p.R17W) alteration is located in exon 1 (coding exon 1) of the NHS gene. This alteration results from a C to T substitution at nucleotide position 49, causing the arginine (R) at amino acid position 17 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Jun 01, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.26
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Vest4		0.37
MVP		0.27
MPC		1.1
ClinPred		0.68	D
GERP RS		-0.43
PromoterAI		-0.0011	Neutral
gMVP		0.10
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs794726963; hg19: chrX-17393929;