X-17726497-T-TA

Variant names:

• chrX-17726497-T-TA
• rs1556038952
• NM_001291867.2:c.2393dupA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001291867.2(NHS):​c.2393dupA​(p.Ser799GlufsTer55) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: NHS NM_001291867.2 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.89
• 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

ENSG00000309710 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291867.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHS	NM_001291867.2	MANE Select	c.2393dupA	p.Ser799GlufsTer55	frameshift	Exon 7 of 9	NP_001278796.1
	NHS	NM_198270.4		c.2330dupA	p.Ser778GlufsTer55	frameshift	Exon 6 of 8	NP_938011.1
	NHS	NM_001440780.1		c.2054dupA	p.Ser686GlufsTer55	frameshift	Exon 7 of 9	NP_001427709.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHS	ENST00000676302.1	MANE Select	c.2393dupA	p.Ser799GlufsTer55	frameshift	Exon 7 of 9	ENSP00000502262.1
	NHS	ENST00000380060.7	TSL:1	c.2330dupA	p.Ser778GlufsTer55	frameshift	Exon 6 of 8	ENSP00000369400.3
	NHS	ENST00000398097.7	TSL:1	c.1862dupA	p.Ser622GlufsTer55	frameshift	Exon 7 of 9	ENSP00000381170.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.9

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: rs1556038952; hg19: chrX-17744617;