dbSNP rs587780401: NHS:p.Ala115_Ala117del (chrX-17376088-TCGGCGGCGG-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.51

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: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001291867.2

BS2

High AC in GnomAdExome4 at 9 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.342_350delGGCGGCGGC	p.Ala115_Ala117del	disruptive_inframe_deletion	Exon 1 of 9	NP_001278796.1	Q6T4R5-1
	NHS	NM_198270.4		c.342_350delGGCGGCGGC	p.Ala115_Ala117del	disruptive_inframe_deletion	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.342_350delGGCGGCGGC	p.Ala115_Ala117del	disruptive_inframe_deletion	Exon 1 of 9	ENSP00000502262.1	Q6T4R5-1
	NHS	ENST00000380060.7	TSL:1	c.342_350delGGCGGCGGC	p.Ala115_Ala117del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000369400.3	Q6T4R5-2

Frequencies

GnomAD3 genomes

AF:

0.0000362

AC:

AN:

110367

Hom.:

Cov.:

show subpopulations

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:

AN:

32481

AF XY:

0.00

show subpopulations

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:

AN:

968025

Hom.:

AF XY:

0.00000652

AC XY:

AN XY:

306971

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20409

American (AMR)

AF:

0.00

AC:

AN:

16638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15684

East Asian (EAS)

AF:

0.00

AC:

AN:

22135

South Asian (SAS)

AF:

0.00

AC:

AN:

39293

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24428

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2701

European-Non Finnish (NFE)

AF:

0.00000891

AC:

AN:

786023

Other (OTH)

AF:

0.0000491

AC:

AN:

40714

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.0000362

AC:

AN:

110367

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

33339

show subpopulations

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

African (AFR)

AF:

0.0000330

AC:

AN:

30340

American (AMR)

AF:

0.00

AC:

AN:

10615

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2620

East Asian (EAS)

AF:

0.00

AC:

AN:

3428

South Asian (SAS)

AF:

0.00

AC:

AN:

2676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5829

Middle Eastern (MID)

AF:

0.00

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.0000572

AC:

AN:

52473

Other (OTH)

AF:

0.00

AC:

AN:

1475

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000102688), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.5

Mutation Taster

=193/7

polymorphism

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over