Genetic Variant NM_001291867.2:c.107C>A (chrX-17375864-C-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.107C>A(p.Pro36Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P36R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

NHS
NM_001291867.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.411

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=0.1500631).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2 link	c.107C>A	p.Pro36Gln	missense_variant	Exon 1 of 9	ENST00000676302.1	NP_001278796.1	Q6T4R5-1
NHS	NM_198270.4 link	c.107C>A	p.Pro36Gln	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.107C>A	p.Pro36Gln	missense_variant	Exon 1 of 9		NM_001291867.2	ENSP00000502262.1		Q6T4R5-1
NHS	ENST00000380060.7 link	c.107C>A	p.Pro36Gln	missense_variant	Exon 1 of 8	1		ENSP00000369400.3		Q6T4R5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

59885

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1004513

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

323209

African (AFR)

AF:

0.00

AC:

AN:

21351

American (AMR)

AF:

0.00

AC:

AN:

22646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16685

East Asian (EAS)

AF:

0.00

AC:

AN:

24357

South Asian (SAS)

AF:

0.00

AC:

AN:

44780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25088

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2715

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

804437

Other (OTH)

AF:

0.00

AC:

AN:

42454

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

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Uncertain

0.98

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.47

M_CAP

Benign

0.064

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

PhyloP100

0.41

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.15

REVEL

Benign

0.029

Sift

Benign

0.18

Sift4G

Benign

0.27

Vest4

0.29

MutPred

0.20

Loss of glycosylation at P36 (P = 0.0046);

MVP

0.25

MPC

0.91

ClinPred

0.48

GERP RS

2.7

PromoterAI

-0.062

Neutral

(source)

gMVP

0.083

Mutation Taster

=93/7

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over