rs149244552

Variant names:

• chrX-17726937-A-T
• rs149244552
• NM_001291867.2:c.2831A>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.2831A>T​(p.His944Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00238 in 1,210,476 control chromosomes in the GnomAD database, including 58 homozygotes. There are 811 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (7 hom., 138 hem., cov: 23)
  • Exomes 𝑓: 0.0022 (51 hom. 673 hem.)
• Consequence: NHS NM_001291867.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.15
• Publications: 7 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=0.017300189).
• BP6: Variant X-17726937-A-T is Benign according to our data. Variant chrX-17726937-A-T is described in ClinVar as Benign. ClinVar VariationId is 129773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0527 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.2831A>T	p.His944Leu	missense	Exon 7 of 9	NP_001278796.1	Q6T4R5-1
	NHS	NM_198270.4		c.2768A>T	p.His923Leu	missense	Exon 6 of 8	NP_938011.1	Q6T4R5-2
	NHS	NM_001440780.1		c.2492A>T	p.His831Leu	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.2831A>T	p.His944Leu	missense	Exon 7 of 9	ENSP00000502262.1	Q6T4R5-1
	NHS	ENST00000380060.7	TSL:1	c.2768A>T	p.His923Leu	missense	Exon 6 of 8	ENSP00000369400.3	Q6T4R5-2
	NHS	ENST00000398097.7	TSL:1	c.2300A>T	p.His767Leu	missense	Exon 7 of 9	ENSP00000381170.3	Q6T4R5-3

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 455 AN: 112177 Hom.: 5 Cov.: 23

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0362

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00561

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00661

GnomAD2 exomes AF: 0.00904 AC: 1657 AN: 183323 AF XY: 0.00676

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.0574

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00216

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000856

Gnomad OTH exome AF: 0.00728

GnomAD4 exome AF: 0.00220 AC: 2411 AN: 1098245 Hom.: 51 Cov.: 33 AF XY: 0.00185 AC XY: 673 AN XY: 363599

African (AFR) AF: 0.000530 AC: 14 AN: 26403

American (AMR) AF: 0.0548 AC: 1928 AN: 35207

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

East Asian (EAS) AF: 0.0110 AC: 332 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

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

European-Non Finnish (NFE) AF: 0.0000534 AC: 45 AN: 842132

Other (OTH) AF: 0.00200 AC: 92 AN: 46097

GnomAD4 genome AF: 0.00414 AC: 465 AN: 112231 Hom.: 7 Cov.: 23 AF XY: 0.00401 AC XY: 138 AN XY: 34381

African (AFR) AF: 0.00113 AC: 35 AN: 30912

American (AMR) AF: 0.0371 AC: 394 AN: 10623

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00563 AC: 20 AN: 3552

South Asian (SAS) AF: 0.00 AC: 0 AN: 2679

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6115

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53261

Other (OTH) AF: 0.00653 AC: 10 AN: 1532

Alfa AF: 0.00221 Hom.: 12

Bravo AF: 0.00724

ESP6500AA AF: 0.00104 AC: 4

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.00615 AC: 747

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Nance-Horan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.70	T
PhyloP100		7.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.045	D
Vest4		0.48
MVP		0.74
MPC		0.60
ClinPred		0.035	T
GERP RS		5.9
gMVP		0.43
Mutation Taster		=99/1	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: rs149244552; hg19: chrX-17745057;