X-17376270-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_001291867.2(NHS):c.513C>T(p.Leu171Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000518 in 1,164,187 control chromosomes in the GnomAD database, including 1 homozygotes. There are 237 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., 18 hem., cov: 23)

Exomes 𝑓: 0.00052 ( 1 hom. 219 hem. )

Consequence

NHS
NM_001291867.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.0610

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant X-17376270-C-T is Benign according to our data. Variant chrX-17376270-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96643.We mark this variant Benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=3}.

BP7

Synonymous conserved (PhyloP=-0.061 with no splicing effect.

BS2

High AC in GnomAd4 at 59 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2 link	c.513C>T	p.Leu171Leu	synonymous_variant	Exon 1 of 9	ENST00000676302.1	NP_001278796.1	Q6T4R5-1
NHS	NM_198270.4 link	c.513C>T	p.Leu171Leu	synonymous_variant	Exon 1 of 8		NP_938011.1	Q6T4R5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1 link	c.513C>T	p.Leu171Leu	synonymous_variant	Exon 1 of 9		NM_001291867.2	ENSP00000502262.1		Q6T4R5-1
NHS	ENST00000380060.7 link	c.513C>T	p.Leu171Leu	synonymous_variant	Exon 1 of 8	1		ENSP00000369400.3		Q6T4R5-2

Frequencies

GnomAD3 genomes

AF:

0.000518

AC:

AN:

112043

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000279

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00147

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00847

Gnomad NFE

AF:

0.000887

Gnomad OTH

AF:

0.000663

GnomAD2 exomes

AF:

0.000586

AC:

AN:

105748

AF XY:

0.000633

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000807

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000746

Gnomad OTH exome

AF:

0.00189

GnomAD4 exome

AF:

0.000517

AC:

544

AN:

1052098

Hom.:

Cov.:

AF XY:

0.000641

AC XY:

219

AN XY:

341730

show subpopulations

African (AFR)

AF:

0.0000392

AC:

AN:

25503

American (AMR)

AF:

0.000891

AC:

AN:

30301

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18763

East Asian (EAS)

AF:

0.00

AC:

AN:

28126

South Asian (SAS)

AF:

0.000655

AC:

AN:

50410

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26182

Middle Eastern (MID)

AF:

0.00427

AC:

AN:

3981

European-Non Finnish (NFE)

AF:

0.000528

AC:

435

AN:

824212

Other (OTH)

AF:

0.000695

AC:

AN:

44620

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000526

AC:

AN:

112089

Hom.:

Cov.:

AF XY:

0.000525

AC XY:

AN XY:

34307

show subpopulations

African (AFR)

AF:

0.0000323

AC:

AN:

30951

American (AMR)

AF:

0.000279

AC:

AN:

10767

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3497

South Asian (SAS)

AF:

0.00147

AC:

AN:

2719

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6099

Middle Eastern (MID)

AF:

0.00926

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000906

AC:

AN:

52987

Other (OTH)

AF:

0.000654

AC:

AN:

1528

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

Alfa

AF:

0.000261

Hom.:

Bravo

AF:

0.000442

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Aug 29, 2013

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NHS: BP4, BP7, BS2 -

not specified

Benign:1

Mar 04, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jul 23, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

Aug 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.0

(source)

DANN

Benign

0.97

PhyloP100

-0.061

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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X-17376270-C-T

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