rs10590816

Positions:

• chrX-17375961-ACCG-A
• chrX-17375961-ACCG-ACCGCCG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001291867.2(NHS):​c.216_218delGCC​(p.Pro73del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00632 in 1,071,997 control chromosomes in the GnomAD database, including 297 homozygotes. There are 1,744 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (153 hom., 958 hem., cov: 21)
  • Exomes 𝑓: 0.0033 (144 hom. 786 hem.)
• Consequence: NHS NM_001291867.2 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.20

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 Benign. Variant got -16 ACMG points.

• BP6: Variant X-17375961-ACCG-A is Benign according to our data. Variant chrX-17375961-ACCG-A is described in ClinVar as [Likely_benign]. Clinvar id is 96635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-17375961-ACCG-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHS	NM_001291867.2	c.216_218delGCC	p.Pro73del	disruptive_inframe_deletion	1/9	ENST00000676302.1	NP_001278796.1
NHS	NM_198270.4	c.216_218delGCC	p.Pro73del	disruptive_inframe_deletion	1/8		NP_938011.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1	c.216_218delGCC	p.Pro73del	disruptive_inframe_deletion	1/9		NM_001291867.2	ENSP00000502262.1
NHS	ENST00000380060.7	c.216_218delGCC	p.Pro73del	disruptive_inframe_deletion	1/8	1		ENSP00000369400.3

Frequencies

GnomAD3 genomes AF: 0.0324 AC: 3570 AN: 110092 Hom.: 153 Cov.: 21 AF XY: 0.0289 AC XY: 951 AN XY: 32952

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00113

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00437

Gnomad NFE AF: 0.000343

Gnomad OTH AF: 0.0246

GnomAD3 exomes AF: 0.00377 AC: 186 AN: 49359 Hom.: 5 AF XY: 0.00276 AC XY: 49 AN XY: 17765

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.00690

Gnomad ASJ exome AF: 0.000228

Gnomad EAS exome AF: 0.00244

Gnomad SAS exome AF: 0.000901

Gnomad FIN exome AF: 0.000606

Gnomad NFE exome AF: 0.000565

Gnomad OTH exome AF: 0.00739

GnomAD4 exome AF: 0.00333 AC: 3202 AN: 961861 Hom.: 144 AF XY: 0.00256 AC XY: 786 AN XY: 307081

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.00977

Gnomad4 ASJ exome AF: 0.000125

Gnomad4 EAS exome AF: 0.0000988

Gnomad4 SAS exome AF: 0.000840

Gnomad4 FIN exome AF: 0.000210

Gnomad4 NFE exome AF: 0.000152

Gnomad4 OTH exome AF: 0.00889

GnomAD4 genome AF: 0.0325 AC: 3577 AN: 110136 Hom.: 153 Cov.: 21 AF XY: 0.0290 AC XY: 958 AN XY: 33006

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.0159

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00113

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000344

Gnomad4 OTH AF: 0.0243

Alfa AF: 0.00694 Hom.: 38

Asia WGS AF: 0.00592 AC: 14 AN: 2375

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 26, 2014	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Nance-Horan syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs10590816; hg19: chrX-17394084;