Genetic Variant NM_001291867.2:c.513C>T (chrX-17376270-C-T) – ACMG Classification: Benign (-10 pts)

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: 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 -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 VariationId is 96643.

BP7

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

BS2

High AC in GnomAd4 at 59 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.513C>T	p.Leu171Leu	synonymous	Exon 1 of 9	NP_001278796.1	Q6T4R5-1
	NHS	NM_198270.4		c.513C>T	p.Leu171Leu	synonymous	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.513C>T	p.Leu171Leu	synonymous	Exon 1 of 9	ENSP00000502262.1	Q6T4R5-1
	NHS	ENST00000380060.7	TSL:1	c.513C>T	p.Leu171Leu	synonymous	Exon 1 of 8	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

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000526

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

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:

0.000261

Hom.:

Bravo

AF:

0.000442

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

Nance-Horan syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over