rs56908561

Positions:

• chrX-17727307-T-C

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.3201T>C​(p.Ser1067=) 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 1,210,146 control chromosomes in the GnomAD database, including 198 homozygotes. There are 1,804 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., 841 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:5
• Conservation: PhyloP100: 0.575

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=-0.92).
• BP6: Variant X-17727307-T-C is Benign according to our data. Variant chrX-17727307-T-C is described in ClinVar as [Benign]. Clinvar id is 129774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-17727307-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.575 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHS	NM_001291867.2	c.3201T>C	p.Ser1067=	synonymous_variant	7/9	ENST00000676302.1	NP_001278796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1	c.3201T>C	p.Ser1067=	synonymous_variant	7/9		NM_001291867.2	ENSP00000502262	P4

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 3058 AN: 112108 Hom.: 111 Cov.: 23 AF XY: 0.0245 AC XY: 839 AN XY: 34292

Gnomad AFR AF: 0.0917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.0117

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000372

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.000413

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.00860 AC: 1576 AN: 183211 Hom.: 51 AF XY: 0.00585 AC XY: 396 AN XY: 67739

Gnomad AFR exome AF: 0.0948

Gnomad AMR exome AF: 0.00773

Gnomad ASJ exome AF: 0.00709

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: 3613 AN: 1097986 Hom.: 87 Cov.: 32 AF XY: 0.00265 AC XY: 963 AN XY: 363346

Gnomad4 AFR exome AF: 0.0932

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: 0.000339

Gnomad4 OTH exome AF: 0.00831

GnomAD4 genome AF: 0.0273 AC: 3057 AN: 112160 Hom.: 111 Cov.: 23 AF XY: 0.0245 AC XY: 841 AN XY: 34354

Gnomad4 AFR AF: 0.0915

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.0117

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000374

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000413

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0130 Hom.: 96

Bravo AF: 0.0320

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.9
DANN	Benign	0.63

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: rs56908561; hg19: chrX-17745427;