rs56691712

chrX-17727310-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001291867.2(NHS):c.3204A>G(p.Leu1068=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00551 in 1,210,009 control chromosomes in the GnomAD database, including 198 homozygotes. There are 1,801 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (111 hom., 838 hem., cov: 23)
  • Exomes 𝑓: 0.0033 (87 hom. 963 hem.)
• Consequence: NHS NM_001291867.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0930

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-17727310-A-G is Benign according to our data. Variant chrX-17727310-A-G is described in ClinVar as [Benign]. Clinvar id is 129775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-17727310-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.093 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHS	NM_001291867.2	c.3204A>G	p.Leu1068=	synonymous_variant	7/9	ENST00000676302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHS	ENST00000676302.1	c.3204A>G	p.Leu1068=	synonymous_variant	7/9		NM_001291867.2	P4

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 3053 AN: 112123 Hom.: 111 Cov.: 23 AF XY: 0.0244 AC XY: 836 AN XY: 34307

Gnomad AFR AF: 0.0916

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0117

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000371

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.000413

Gnomad OTH AF: 0.0198

GnomAD3 exomes AF: 0.00861 AC: 1577 AN: 183198 Hom.: 51 AF XY: 0.00586 AC XY: 397 AN XY: 67734

Gnomad AFR exome AF: 0.0948

Gnomad AMR exome AF: 0.00777

Gnomad ASJ exome AF: 0.00710

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00641

GnomAD4 exome AF: 0.00329 AC: 3611 AN: 1097833 Hom.: 87 Cov.: 32 AF XY: 0.00265 AC XY: 963 AN XY: 363193

Gnomad4 AFR exome AF: 0.0931

Gnomad4 AMR exome AF: 0.00909

Gnomad4 ASJ exome AF: 0.00722

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000337

Gnomad4 OTH exome AF: 0.00831

GnomAD4 genome AF: 0.0272 AC: 3052 AN: 112176 Hom.: 111 Cov.: 23 AF XY: 0.0244 AC XY: 838 AN XY: 34370

Gnomad4 AFR AF: 0.0914

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.0117

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000373

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000413

Gnomad4 OTH AF: 0.0196

Alfa AF: 0.0118 Hom.: 89

Bravo AF: 0.0320

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2014

This alteration is classified as 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

Invitae

Jan 30, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	3.4
Dann	Benign	0.77

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: rs56691712; hg19: chrX-17745430;