NM_001291867.2:c.1714C>T

Variant names:

• chrX-17725820-C-T
• rs150688899
• NM_001291867.2:c.1714C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001291867.2(NHS):​c.1714C>T​(p.Pro572Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0219 in 1,209,406 control chromosomes in the GnomAD database, including 888 homozygotes. There are 7,921 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (413 hom., 1753 hem., cov: 22)
  • Exomes 𝑓: 0.018 (475 hom. 6168 hem.)
• Consequence: NHS NM_001291867.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.86
• Publications: 5 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000309710 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016627014).
• BP6: Variant X-17725820-C-T is Benign according to our data. Variant chrX-17725820-C-T is described in ClinVar as Benign. ClinVar VariationId is 96632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

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.1714C>T	p.Pro572Ser	missense	Exon 7 of 9	NP_001278796.1	Q6T4R5-1
	NHS	NM_198270.4		c.1651C>T	p.Pro551Ser	missense	Exon 6 of 8	NP_938011.1	Q6T4R5-2
	NHS	NM_001440780.1		c.1375C>T	p.Pro459Ser	missense	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.1714C>T	p.Pro572Ser	missense	Exon 7 of 9	ENSP00000502262.1	Q6T4R5-1
	NHS	ENST00000380060.7	TSL:1	c.1651C>T	p.Pro551Ser	missense	Exon 6 of 8	ENSP00000369400.3	Q6T4R5-2
	NHS	ENST00000398097.7	TSL:1	c.1183C>T	p.Pro395Ser	missense	Exon 7 of 9	ENSP00000381170.3	Q6T4R5-3

Frequencies

GnomAD3 genomes AF: 0.0614 AC: 6822 AN: 111142 Hom.: 413 Cov.: 22

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.00294

Gnomad AMR AF: 0.0326

Gnomad ASJ AF: 0.00378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00803

Gnomad FIN AF: 0.00929

Gnomad MID AF: 0.0549

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.0694

GnomAD2 exomes AF: 0.0253 AC: 4619 AN: 182822 AF XY: 0.0212

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.00227

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00889

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0228

GnomAD4 exome AF: 0.0179 AC: 19630 AN: 1098211 Hom.: 475 Cov.: 33 AF XY: 0.0170 AC XY: 6168 AN XY: 363565

African (AFR) AF: 0.190 AC: 5023 AN: 26401

American (AMR) AF: 0.0163 AC: 575 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00160 AC: 31 AN: 19386

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30205

South Asian (SAS) AF: 0.00885 AC: 479 AN: 54148

European-Finnish (FIN) AF: 0.00901 AC: 365 AN: 40523

Middle Eastern (MID) AF: 0.0580 AC: 240 AN: 4135

European-Non Finnish (NFE) AF: 0.0139 AC: 11733 AN: 842114

Other (OTH) AF: 0.0257 AC: 1183 AN: 46094

GnomAD4 genome AF: 0.0613 AC: 6819 AN: 111195 Hom.: 413 Cov.: 22 AF XY: 0.0524 AC XY: 1753 AN XY: 33435

African (AFR) AF: 0.181 AC: 5499 AN: 30423

American (AMR) AF: 0.0325 AC: 344 AN: 10573

Ashkenazi Jewish (ASJ) AF: 0.00378 AC: 10 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3526

South Asian (SAS) AF: 0.00806 AC: 21 AN: 2606

European-Finnish (FIN) AF: 0.00929 AC: 56 AN: 6030

Middle Eastern (MID) AF: 0.0556 AC: 12 AN: 216

European-Non Finnish (NFE) AF: 0.0146 AC: 772 AN: 52991

Other (OTH) AF: 0.0685 AC: 103 AN: 1504

Alfa AF: 0.0329 Hom.: 2008

Bravo AF: 0.0695

TwinsUK AF: 0.0175 AC: 65

ALSPAC AF: 0.0170 AC: 49

ESP6500AA AF: 0.191 AC: 734

ESP6500EA AF: 0.0149 AC: 100

ExAC AF: 0.0286 AC: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Nance-Horan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.2	T
PhyloP100		5.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.25
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.024	D
Vest4		0.46
MPC		0.45
ClinPred		0.018	T
GERP RS		5.9
gMVP		0.67
Mutation Taster		=93/7	polymorphism (auto)

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: rs150688899; hg19: chrX-17743940;