Genetic Variant NHS:p.Ala117dup (chrX-17376088-T-TCGG) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3BP6_Very_StrongBS2

The NM_001291867.2(NHS):c.348_350dupGGC(p.Ala117dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,078,419 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 36 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.00011 ( 0 hom. 30 hem. )

Consequence

NHS
NM_001291867.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.485

Publications

1 publications found

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]

NHS Gene-Disease associations (from GenCC):

Nance-Horan syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Ambry Genetics
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NHS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001291867.2

BP6

Variant X-17376088-T-TCGG is Benign according to our data. Variant chrX-17376088-T-TCGG is described in ClinVar as Likely_benign. ClinVar VariationId is 588878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 30 XL,AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHS	NM_001291867.2	MANE Select	c.348_350dupGGC	p.Ala117dup	disruptive_inframe_insertion	Exon 1 of 9	NP_001278796.1	Q6T4R5-1
	NHS	NM_198270.4		c.348_350dupGGC	p.Ala117dup	disruptive_inframe_insertion	Exon 1 of 8	NP_938011.1	Q6T4R5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHS	ENST00000676302.1	MANE Select	c.348_350dupGGC	p.Ala117dup	disruptive_inframe_insertion	Exon 1 of 9	ENSP00000502262.1	Q6T4R5-1
	NHS	ENST00000380060.7	TSL:1	c.348_350dupGGC	p.Ala117dup	disruptive_inframe_insertion	Exon 1 of 8	ENSP00000369400.3	Q6T4R5-2

Frequencies

GnomAD3 genomes

AF:

0.000272

AC:

AN:

110366

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000363

Gnomad AMI

AF:

0.00443

Gnomad AMR

AF:

0.000471

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000875

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000152

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000246

AC:

AN:

32481

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000793

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00114

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000759

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000114

AC:

110

AN:

968013

Hom.:

Cov.:

AF XY:

0.0000977

AC XY:

AN XY:

306963

show subpopulations

African (AFR)

AF:

0.000490

AC:

AN:

20409

American (AMR)

AF:

0.000721

AC:

AN:

16637

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15684

East Asian (EAS)

AF:

0.00117

AC:

AN:

22135

South Asian (SAS)

AF:

0.000153

AC:

AN:

39292

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24428

Middle Eastern (MID)

AF:

0.000370

AC:

AN:

2701

European-Non Finnish (NFE)

AF:

0.0000662

AC:

AN:

786016

Other (OTH)

AF:

0.0000737

AC:

AN:

40711

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000272

AC:

AN:

110406

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

AN XY:

33392

show subpopulations

African (AFR)

AF:

0.000362

AC:

AN:

30399

American (AMR)

AF:

0.000470

AC:

AN:

10630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2620

East Asian (EAS)

AF:

0.000879

AC:

AN:

3413

South Asian (SAS)

AF:

0.00

AC:

AN:

2670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5829

Middle Eastern (MID)

AF:

0.00

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.000152

AC:

AN:

52464

Other (OTH)

AF:

0.00

AC:

AN:

1491

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000453

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Nance-Horan syndrome (1)

NHS-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.48

Mutation Taster

=85/15

polymorphism

(source)

Splicing

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

Publications

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X-17376088-TCGGCGGCGG-TCGGCGGCGGCGG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over