Genetic Variant NM_001291867.2:c.566-95005T>C (chrX-17592737-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001291867.2(NHS):c.566-95005T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00697 in 111,847 control chromosomes in the GnomAD database, including 6 homozygotes. There are 226 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0070 ( 6 hom., 226 hem., cov: 22)

Consequence

NHS
NM_001291867.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.140

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00697 (780/111847) while in subpopulation SAS AF = 0.0247 (66/2676). AF 95% confidence interval is 0.0199. There are 6 homozygotes in GnomAd4. There are 226 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 780 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2 link	c.566-95005T>C		intron_variant	Intron 1 of 8	ENST00000676302.1	NP_001278796.1	Q6T4R5-1
NHS	NM_198270.4 link	c.566-95005T>C		intron_variant	Intron 1 of 7		NP_938011.1	Q6T4R5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1 link	c.566-95005T>C		intron_variant	Intron 1 of 8		NM_001291867.2	ENSP00000502262.1		Q6T4R5-1
NHS	ENST00000380060.7 link	c.566-95005T>C		intron_variant	Intron 1 of 7	1		ENSP00000369400.3		Q6T4R5-2

Frequencies

GnomAD3 genomes

AF:

0.00697

AC:

779

AN:

111796

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00456

Gnomad ASJ

AF:

0.0348

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0242

Gnomad FIN

AF:

0.00298

Gnomad MID

AF:

0.0546

Gnomad NFE

AF:

0.00921

Gnomad OTH

AF:

0.0133

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.00697

AC:

780

AN:

111847

Hom.:

Cov.:

AF XY:

0.00664

AC XY:

226

AN XY:

34043

show subpopulations

African (AFR)

AF:

0.00107

AC:

AN:

30785

American (AMR)

AF:

0.00456

AC:

AN:

10534

Ashkenazi Jewish (ASJ)

AF:

0.0348

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3568

South Asian (SAS)

AF:

0.0247

AC:

AN:

2676

European-Finnish (FIN)

AF:

0.00298

AC:

AN:

6042

Middle Eastern (MID)

AF:

0.0599

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00922

AC:

490

AN:

53173

Other (OTH)

AF:

0.0132

AC:

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

118

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:

0.00855

Hom.:

Bravo

AF:

0.00633

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.6

(source)

DANN

Benign

0.61

PhyloP100

-0.14

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over