rs587780401

Variant names:

• chrX-17376088-TCGGCGGCGG-T
• rs587780401
• NM_001291867.2:c.342_350delGGCGGCGGC

Your query was ambiguous. Multiple possible variants found:

• chrX-17376088-TCGGCGGCGG-T
• chrX-17376088-TCGGCGGCGG-TCGG
• chrX-17376088-TCGGCGGCGG-TCGGCGG
• chrX-17376088-TCGGCGGCGG-TCGGCGGCGGCGG
• chrX-17376088-TCGGCGGCGG-TCGGCGGCGGCGGCGG
• chrX-17376088-TCGGCGGCGG-TCGGCGGCGGCGGCGGCGG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001291867.2(NHS):​c.342_350delGGCGGCGGC​(p.Ala115_Ala117del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,078,392 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000093 (0 hom. 2 hem.)
• Consequence: NHS NM_001291867.2 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51
• Publications: 1 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 -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 9 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2	c.342_350delGGCGGCGGC	p.Ala115_Ala117del	disruptive_inframe_deletion	Exon 1 of 9	ENST00000676302.1	NP_001278796.1
NHS	NM_198270.4	c.342_350delGGCGGCGGC	p.Ala115_Ala117del	disruptive_inframe_deletion	Exon 1 of 8		NP_938011.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1	c.342_350delGGCGGCGGC	p.Ala115_Ala117del	disruptive_inframe_deletion	Exon 1 of 9		NM_001291867.2	ENSP00000502262.1
NHS	ENST00000380060.7	c.342_350delGGCGGCGGC	p.Ala115_Ala117del	disruptive_inframe_deletion	Exon 1 of 8	1		ENSP00000369400.3

Frequencies

GnomAD3 genomes AF: 0.0000362 AC: 4 AN: 110367 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000330

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: 0.0000572

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000308 AC: 1 AN: 32481 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000759

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000930 AC: 9 AN: 968025 Hom.: 0 AF XY: 0.00000652 AC XY: 2 AN XY: 306971

African (AFR) AF: 0.00 AC: 0 AN: 20409

American (AMR) AF: 0.00 AC: 0 AN: 16638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15684

East Asian (EAS) AF: 0.00 AC: 0 AN: 22135

South Asian (SAS) AF: 0.00 AC: 0 AN: 39293

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2701

European-Non Finnish (NFE) AF: 0.00000891 AC: 7 AN: 786023

Other (OTH) AF: 0.0000491 AC: 2 AN: 40714

GnomAD4 genome AF: 0.0000362 AC: 4 AN: 110367 Hom.: 0 Cov.: 23 AF XY: 0.0000300 AC XY: 1 AN XY: 33339

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000330 AC: 1 AN: 30340

American (AMR) AF: 0.00 AC: 0 AN: 10615

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2620

East Asian (EAS) AF: 0.00 AC: 0 AN: 3428

South Asian (SAS) AF: 0.00 AC: 0 AN: 2676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5829

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.0000572 AC: 3 AN: 52473

Other (OTH) AF: 0.00 AC: 0 AN: 1475

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000103), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 17, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5
Mutation Taster		=193/7	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs587780401; hg19: chrX-17394211;