X-17375933-GC-AA

Position:

• chrX-17375933-GC-AA

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001291867.2(NHS):​c.176_177delinsAA​(p.Arg59Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: NHS NM_001291867.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.106

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHS	NM_001291867.2	c.176_177delinsAA	p.Arg59Gln	missense_variant	1/9	ENST00000676302.1	NP_001278796.1
NHS	NM_198270.4	c.176_177delinsAA	p.Arg59Gln	missense_variant	1/8		NP_938011.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1	c.176_177delinsAA	p.Arg59Gln	missense_variant	1/9		NM_001291867.2	ENSP00000502262	P4
NHS	ENST00000380060.7	c.176_177delinsAA	p.Arg59Gln	missense_variant	1/8	1		ENSP00000369400	A2

Frequencies

GnomAD3 genomes Cov.: 23

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

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 01, 2015

- -

Nance-Horan syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 08, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 59 of the NHS protein (p.Arg59Gln). This variant is present in population databases (rs797045739, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with NHS-related conditions. ClinVar contains an entry for this variant (Variation ID: 211596). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Nance-Horan syndrome;C4049004:Cataract 40 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797045739; hg19: chrX-17394056;