chrX-17375806-CGGCG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001291867.2(NHS):​c.50_53del​(p.Arg17ProfsTer178) variant causes a frameshift 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 Pathogenic (★).

Frequency

Genomes: not found (cov: 23)

Consequence

NHS
NM_001291867.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.94
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 25 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-17375806-CGGCG-C is Pathogenic according to our data. Variant chrX-17375806-CGGCG-C is described in ClinVar as [Pathogenic]. Clinvar id is 1446464.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NHSNM_001291867.2 linkuse as main transcriptc.50_53del p.Arg17ProfsTer178 frameshift_variant 1/9 ENST00000676302.1
NHSNM_198270.4 linkuse as main transcriptc.50_53del p.Arg17ProfsTer178 frameshift_variant 1/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NHSENST00000676302.1 linkuse as main transcriptc.50_53del p.Arg17ProfsTer178 frameshift_variant 1/9 NM_001291867.2 P4Q6T4R5-1
NHSENST00000380060.7 linkuse as main transcriptc.50_53del p.Arg17ProfsTer178 frameshift_variant 1/81 A2Q6T4R5-2

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: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Nance-Horan syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeOct 25, 2020For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with NHS-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Arg17Profs*178) in the NHS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NHS are known to be pathogenic (PMID: 14564667, 19414485). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-17393929; API