dbSNP rs147497359: NHS:p.Glu276Glu (chrX-17692444-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_001291867.2(NHS):c.828G>A(p.Glu276Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00026 in 1,207,953 control chromosomes in the GnomAD database, including 1 homozygotes. There are 91 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00086 ( 0 hom., 22 hem., cov: 21)

Exomes 𝑓: 0.00020 ( 1 hom. 69 hem. )

Consequence

NHS
NM_001291867.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.147

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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant X-17692444-G-A is Benign according to our data. Variant chrX-17692444-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.147 with no splicing effect.

BS2

High AC in GnomAd4 at 95 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NHS	NM_001291867.2	MANE Select	c.828G>A	p.Glu276Glu	synonymous	Exon 3 of 9	NP_001278796.1	Q6T4R5-1
NHS	NM_198270.4		c.828G>A	p.Glu276Glu	synonymous	Exon 3 of 8	NP_938011.1	Q6T4R5-2
NHS	NM_001440780.1		c.489G>A	p.Glu163Glu	synonymous	Exon 3 of 9	NP_001427709.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NHS	ENST00000676302.1	MANE Select	c.828G>A	p.Glu276Glu	synonymous	Exon 3 of 9	ENSP00000502262.1	Q6T4R5-1
NHS	ENST00000380060.7	TSL:1	c.828G>A	p.Glu276Glu	synonymous	Exon 3 of 8	ENSP00000369400.3	Q6T4R5-2
NHS	ENST00000398097.7	TSL:1	c.297G>A	p.Glu99Glu	synonymous	Exon 3 of 9	ENSP00000381170.3	Q6T4R5-3

Frequencies

GnomAD3 genomes

AF:

0.000865

AC:

AN:

109810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00253

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000390

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0128

Gnomad NFE

AF:

0.000171

Gnomad OTH

AF:

0.00205

GnomAD2 exomes

AF:

0.000414

AC:

AN:

183444

AF XY:

0.000339

show subpopulations

Gnomad AFR exome

AF:

0.00319

Gnomad AMR exome

AF:

0.000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.000882

GnomAD4 exome

AF:

0.000199

AC:

219

AN:

1098089

Hom.:

Cov.:

AF XY:

0.000190

AC XY:

AN XY:

363477

show subpopulations

African (AFR)

AF:

0.00273

AC:

AN:

26398

American (AMR)

AF:

0.000341

AC:

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30200

South Asian (SAS)

AF:

0.0000923

AC:

AN:

54146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40522

Middle Eastern (MID)

AF:

0.00508

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.000107

AC:

AN:

842022

Other (OTH)

AF:

0.000412

AC:

AN:

46084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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:

0.000865

AC:

AN:

109864

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

32124

show subpopulations

African (AFR)

AF:

0.00252

AC:

AN:

30147

American (AMR)

AF:

0.000389

AC:

AN:

10280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2627

East Asian (EAS)

AF:

0.00

AC:

AN:

3474

South Asian (SAS)

AF:

0.00

AC:

AN:

2432

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5823

Middle Eastern (MID)

AF:

0.0141

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.000171

AC:

AN:

52709

Other (OTH)

AF:

0.00203

AC:

AN:

1481

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

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:

0.000477

Hom.:

Bravo

AF:

0.00110

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Inborn genetic diseases (1)

Nance-Horan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

5.6

(source)

DANN

Benign

0.47

PhyloP100

0.15

Mutation Taster

=100/0

polymorphism

(source)

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

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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