chrX-17376270-C-T

Position:

• chrX-17376270-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001291867.2(NHS):​c.513C>T​(p.Leu171Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000518 in 1,164,187 control chromosomes in the GnomAD database, including 1 homozygotes. There are 237 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., 18 hem., cov: 23)
  • Exomes 𝑓: 0.00052 (1 hom. 219 hem.)
• Consequence: NHS NM_001291867.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.0610

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant X-17376270-C-T is Benign according to our data. Variant chrX-17376270-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96643.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}. Variant chrX-17376270-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.061 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHS	NM_001291867.2	c.513C>T	p.Leu171Leu	synonymous_variant	1/9	ENST00000676302.1	NP_001278796.1
NHS	NM_198270.4	c.513C>T	p.Leu171Leu	synonymous_variant	1/8		NP_938011.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1	c.513C>T	p.Leu171Leu	synonymous_variant	1/9		NM_001291867.2	ENSP00000502262.1
NHS	ENST00000380060.7	c.513C>T	p.Leu171Leu	synonymous_variant	1/8	1		ENSP00000369400.3

Frequencies

GnomAD3 genomes AF: 0.000518 AC: 58 AN: 112043 Hom.: 0 Cov.: 23 AF XY: 0.000526 AC XY: 18 AN XY: 34251

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000279

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00147

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00847

Gnomad NFE AF: 0.000887

Gnomad OTH AF: 0.000663

GnomAD3 exomes AF: 0.000586 AC: 62 AN: 105748 Hom.: 0 AF XY: 0.000633 AC XY: 22 AN XY: 34738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000807

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000564

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000746

Gnomad OTH exome AF: 0.00189

GnomAD4 exome AF: 0.000517 AC: 544 AN: 1052098 Hom.: 1 Cov.: 32 AF XY: 0.000641 AC XY: 219 AN XY: 341730

Gnomad4 AFR exome AF: 0.0000392

Gnomad4 AMR exome AF: 0.000891

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000655

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000528

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.000526 AC: 59 AN: 112089 Hom.: 0 Cov.: 23 AF XY: 0.000525 AC XY: 18 AN XY: 34307

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.000279

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00147

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000906

Gnomad4 OTH AF: 0.000654

Alfa AF: 0.000261 Hom.: 2

Bravo AF: 0.000442

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 29, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	NHS: BP4, BP7, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 04, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 23, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Nance-Horan syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.0
DANN	Benign	0.97

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

LitVar

Other links and lift over

dbSNP: rs398124610; hg19: chrX-17394393;