X-17375904-C-T

Variant names:

• chrX-17375904-C-T
• rs794726961
• NM_001291867.2:c.147C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001291867.2(NHS):​c.147C>T​(p.Val49Val) variant causes a synonymous 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. Variant has been reported in ClinVar 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 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0450
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP7: Synonymous conserved (PhyloP=-0.045 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2	c.147C>T	p.Val49Val	synonymous_variant	Exon 1 of 9	ENST00000676302.1	NP_001278796.1
NHS	NM_198270.4	c.147C>T	p.Val49Val	synonymous_variant	Exon 1 of 8		NP_938011.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1	c.147C>T	p.Val49Val	synonymous_variant	Exon 1 of 9		NM_001291867.2	ENSP00000502262.1
NHS	ENST00000380060.7	c.147C>T	p.Val49Val	synonymous_variant	Exon 1 of 8	1		ENSP00000369400.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 984560 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 315912

African (AFR) AF: 0.00 AC: 0 AN: 20609

American (AMR) AF: 0.00 AC: 0 AN: 19591

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15904

East Asian (EAS) AF: 0.00 AC: 0 AN: 22700

South Asian (SAS) AF: 0.00 AC: 0 AN: 42496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24783

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2666

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 794455

Other (OTH) AF: 0.00 AC: 0 AN: 41356

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 01, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.7
DANN	Benign	0.94
PhyloP100		-0.045
PromoterAI		-0.015	Neutral

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

Other links and lift over

dbSNP: rs794726961; hg19: chrX-17394027;