rs1157246576

Variant names:

• chrX-17727199-G-A
• rs1157246576
• NM_001291867.2:c.3093G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001291867.2(NHS):​c.3093G>A​(p.Thr1031Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,209,116 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 2 hem.)
• Consequence: NHS NM_001291867.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.96
• 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

ENSG00000309710 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-17727199-G-A is Benign according to our data. Variant chrX-17727199-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 435990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.96 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 11 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291867.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHS	NM_001291867.2	MANE Select	c.3093G>A	p.Thr1031Thr	synonymous	Exon 7 of 9	NP_001278796.1
	NHS	NM_198270.4		c.3030G>A	p.Thr1010Thr	synonymous	Exon 6 of 8	NP_938011.1
	NHS	NM_001440780.1		c.2754G>A	p.Thr918Thr	synonymous	Exon 7 of 9	NP_001427709.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHS	ENST00000676302.1	MANE Select	c.3093G>A	p.Thr1031Thr	synonymous	Exon 7 of 9	ENSP00000502262.1
	NHS	ENST00000380060.7	TSL:1	c.3030G>A	p.Thr1010Thr	synonymous	Exon 6 of 8	ENSP00000369400.3
	NHS	ENST00000398097.7	TSL:1	c.2562G>A	p.Thr854Thr	synonymous	Exon 7 of 9	ENSP00000381170.3

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 110958 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183217 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

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 AF: 0.0000100 AC: 11 AN: 1098158 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 2 AN XY: 363512

African (AFR) AF: 0.000152 AC: 4 AN: 26398

American (AMR) AF: 0.0000284 AC: 1 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54145

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 842069

Other (OTH) AF: 0.0000434 AC: 2 AN: 46096

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 110958 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33436

African (AFR) AF: 0.0000328 AC: 1 AN: 30485

American (AMR) AF: 0.00 AC: 0 AN: 10467

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2632

East Asian (EAS) AF: 0.00 AC: 0 AN: 3492

South Asian (SAS) AF: 0.00 AC: 0 AN: 2615

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 220

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52840

Other (OTH) AF: 0.00 AC: 0 AN: 1476

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Nance-Horan syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.12
DANN	Benign	0.62
PhyloP100		-2.0

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: rs1157246576; hg19: chrX-17745319;