rs5955543

Variant names:

• chrX-17680277-A-G
• rs5955543
• NM_001291867.2:c.566-7465A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001291867.2(NHS):​c.566-7465A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 111,821 control chromosomes in the GnomAD database, including 2,639 homozygotes. There are 5,400 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2639 hom., 5400 hem., cov: 23)
• Consequence: NHS NM_001291867.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.45
• Publications: 12 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2	c.566-7465A>G		intron_variant	Intron 1 of 8	ENST00000676302.1	NP_001278796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1	c.566-7465A>G		intron_variant	Intron 1 of 8		NM_001291867.2	ENSP00000502262.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 18809 AN: 111766 Hom.: 2633 Cov.: 23

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.0940

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.0567

Gnomad FIN AF: 0.0172

Gnomad MID AF: 0.0714

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.178

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.169 AC: 18846 AN: 111821 Hom.: 2639 Cov.: 23 AF XY: 0.159 AC XY: 5400 AN XY: 34045

African (AFR) AF: 0.439 AC: 13396 AN: 30525

American (AMR) AF: 0.271 AC: 2868 AN: 10601

Ashkenazi Jewish (ASJ) AF: 0.0940 AC: 248 AN: 2638

East Asian (EAS) AF: 0.269 AC: 946 AN: 3523

South Asian (SAS) AF: 0.0580 AC: 157 AN: 2708

European-Finnish (FIN) AF: 0.0172 AC: 106 AN: 6177

Middle Eastern (MID) AF: 0.0783 AC: 17 AN: 217

European-Non Finnish (NFE) AF: 0.0155 AC: 826 AN: 53219

Other (OTH) AF: 0.185 AC: 282 AN: 1526

Alfa AF: 0.0945 Hom.: 9188

Bravo AF: 0.207

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.7
DANN	Benign	0.79
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs5955543; hg19: chrX-17698397;