dbSNP rs1341004065: NHS:p.Glu93Lys (chrX-17376034-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001291867.2(NHS):c.277G>A(p.Glu93Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000103 in 969,444 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000010 ( 0 hom. 0 hem. )

Consequence

NHS
NM_001291867.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.945

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13808644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2 link	c.277G>A	p.Glu93Lys	missense_variant	Exon 1 of 9	ENST00000676302.1	NP_001278796.1
NHS	NM_198270.4 link	c.277G>A	p.Glu93Lys	missense_variant	Exon 1 of 8		NP_938011.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1 link	c.277G>A	p.Glu93Lys	missense_variant	Exon 1 of 9		NM_001291867.2	ENSP00000502262.1
NHS	ENST00000380060.7 link	c.277G>A	p.Glu93Lys	missense_variant	Exon 1 of 8	1		ENSP00000369400.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000103

AC:

AN:

969444

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

308240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20545

American (AMR)

AF:

0.00

AC:

AN:

18616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16146

East Asian (EAS)

AF:

0.00

AC:

AN:

21243

South Asian (SAS)

AF:

0.00

AC:

AN:

40403

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2635

European-Non Finnish (NFE)

AF:

0.00000127

AC:

AN:

784936

Other (OTH)

AF:

0.00

AC:

AN:

40572

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Uncertain

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.63

M_CAP

Benign

0.018

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.94

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

0.090

REVEL

Benign

0.11

Sift

Uncertain

0.025

Sift4G

Benign

0.32

Vest4

0.31

MutPred

0.17

Gain of ubiquitination at E93 (P = 0.0042);

MVP

0.28

MPC

0.43

ClinPred

0.34

GERP RS

2.7

gMVP

0.18

Mutation Taster

=94/6

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over