Genetic Variant NHS:p.Glu55Asp (chrX-17375922-G-C) – 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.165G>C(p.Glu55Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000204 in 979,858 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. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E55E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000020 ( 0 hom. 0 hem. )

Consequence

NHS
NM_001291867.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.709

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:

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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=0.10342315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2 link	c.165G>C	p.Glu55Asp	missense_variant	Exon 1 of 9	ENST00000676302.1	NP_001278796.1	Q6T4R5-1
NHS	NM_198270.4 link	c.165G>C	p.Glu55Asp	missense_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.165G>C	p.Glu55Asp	missense_variant	Exon 1 of 9		NM_001291867.2	ENSP00000502262.1		Q6T4R5-1
NHS	ENST00000380060.7 link	c.165G>C	p.Glu55Asp	missense_variant	Exon 1 of 8	1		ENSP00000369400.3		Q6T4R5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000204

AC:

AN:

979858

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

314050

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20585

American (AMR)

AF:

0.00

AC:

AN:

19519

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16074

East Asian (EAS)

AF:

0.00

AC:

AN:

21821

South Asian (SAS)

AF:

0.00

AC:

AN:

42415

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24636

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2643

European-Non Finnish (NFE)

AF:

0.00000253

AC:

AN:

791166

Other (OTH)

AF:

0.00

AC:

AN:

40999

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.96

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.41

M_CAP

Benign

0.019

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

PhyloP100

0.71

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.12

REVEL

Benign

0.050

Sift

Benign

0.42

Sift4G

Benign

0.14

Vest4

0.13

MutPred

0.14

Gain of stability (P = 0.1447);

MVP

0.20

MPC

1.0

ClinPred

0.051

GERP RS

1.4

gMVP

0.040

Mutation Taster

=96/4

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-17375922-G-C

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