rs143065064

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000398097.7(NHS):c.11C>T(p.Ala4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0056 in 1,165,554 control chromosomes in the GnomAD database, including 14 homozygotes. There are 2,062 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0043 ( 1 hom., 160 hem., cov: 23)

Exomes 𝑓: 0.0057 ( 13 hom. 1902 hem. )

Consequence

NHS
ENST00000398097.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.24

Publications

2 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: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NHS links:

LOC105373142 (HGNC:):

LOC105373142 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005512178).

BP6

Variant X-17635577-C-T is Benign according to our data. Variant chrX-17635577-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 445733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 486 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2 link	c.566-52165C>T		intron_variant	Intron 1 of 8	ENST00000676302.1	NP_001278796.1	Q6T4R5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NHS	ENST00000398097.7 link	c.11C>T	p.Ala4Val	missense_variant	Exon 1 of 9	1		ENSP00000381170.3	Q6T4R5-3
NHS	ENST00000617601.4 link	c.-8C>T		5_prime_UTR_variant	Exon 1 of 8	1		ENSP00000478433.1	A0A087WU78
NHS	ENST00000676302.1 link	c.566-52165C>T		intron_variant	Intron 1 of 8		NM_001291867.2	ENSP00000502262.1	Q6T4R5-1
NHS	ENST00000380060.7 link	c.566-52165C>T		intron_variant	Intron 1 of 7	1		ENSP00000369400.3	Q6T4R5-2

Frequencies

GnomAD3 genomes

AF:

0.00433

AC:

487

AN:

112511

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000775

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00270

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000366

Gnomad FIN

AF:

0.00581

Gnomad MID

AF:

0.0167

Gnomad NFE

AF:

0.00644

Gnomad OTH

AF:

0.00266

GnomAD2 exomes

AF:

0.00441

AC:

492

AN:

111471

AF XY:

0.00468

show subpopulations

Gnomad AFR exome

AF:

0.000475

Gnomad AMR exome

AF:

0.00176

Gnomad ASJ exome

AF:

0.0111

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00629

Gnomad NFE exome

AF:

0.00683

Gnomad OTH exome

AF:

0.00503

GnomAD4 exome

AF:

0.00574

AC:

6040

AN:

1052990

Hom.:

Cov.:

AF XY:

0.00553

AC XY:

1902

AN XY:

343876

show subpopulations

African (AFR)

AF:

0.000522

AC:

AN:

24886

American (AMR)

AF:

0.00190

AC:

AN:

27838

Ashkenazi Jewish (ASJ)

AF:

0.0117

AC:

217

AN:

18602

East Asian (EAS)

AF:

0.00

AC:

AN:

27098

South Asian (SAS)

AF:

0.000624

AC:

AN:

49715

European-Finnish (FIN)

AF:

0.00782

AC:

294

AN:

37613

Middle Eastern (MID)

AF:

0.00370

AC:

AN:

4052

European-Non Finnish (NFE)

AF:

0.00633

AC:

5182

AN:

818858

Other (OTH)

AF:

0.00530

AC:

235

AN:

44328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

239

478

716

955

1194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

368

552

736

920

<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:

0.00432

AC:

486

AN:

112564

Hom.:

Cov.:

AF XY:

0.00461

AC XY:

160

AN XY:

34726

show subpopulations

African (AFR)

AF:

0.000773

AC:

AN:

31049

American (AMR)

AF:

0.00270

AC:

AN:

10739

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3563

South Asian (SAS)

AF:

0.000368

AC:

AN:

2721

European-Finnish (FIN)

AF:

0.00581

AC:

AN:

6197

Middle Eastern (MID)

AF:

0.0138

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00645

AC:

343

AN:

53213

Other (OTH)

AF:

0.00263

AC:

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.00626

Hom.:

289

Bravo

AF:

0.00363

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00312

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00669

AC:

ExAC

AF:

0.00373

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 30, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.53

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.0055

MetaSVM

Benign

-1.1

PhyloP100

2.2

PROVEAN

Benign

0.70

REVEL

Benign

0.024

Sift

Benign

0.15

Sift4G

Benign

0.070

Vest4

0.042

MVP

0.69

ClinPred

0.010

GERP RS

4.2

PromoterAI

-0.038

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over