X-17728124-T-C

Variant names:

• chrX-17728124-T-C
• rs3747295
• NM_001291867.2:c.4018T>C

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.4018T>C​(p.Phe1340Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0892 in 1,209,376 control chromosomes in the GnomAD database, including 20,115 homozygotes. There are 31,843 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (8322 hom., 8960 hem., cov: 22)
  • Exomes 𝑓: 0.069 (11793 hom. 22883 hem.)
• Consequence: NHS NM_001291867.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.101
• Publications: 20 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Ambry Genetics
• 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=6.097197E-7).
• BP6: Variant X-17728124-T-C is Benign according to our data. Variant chrX-17728124-T-C is described in ClinVar as Benign. ClinVar VariationId is 129776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.821 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.4018T>C	p.Phe1340Leu	missense	Exon 7 of 9	NP_001278796.1	Q6T4R5-1
	NHS	NM_198270.4		c.3955T>C	p.Phe1319Leu	missense	Exon 6 of 8	NP_938011.1	Q6T4R5-2
	NHS	NM_001440780.1		c.3679T>C	p.Phe1227Leu	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.4018T>C	p.Phe1340Leu	missense	Exon 7 of 9	ENSP00000502262.1	Q6T4R5-1
	NHS	ENST00000380060.7	TSL:1	c.3955T>C	p.Phe1319Leu	missense	Exon 6 of 8	ENSP00000369400.3	Q6T4R5-2
	NHS	ENST00000398097.7	TSL:1	c.3487T>C	p.Phe1163Leu	missense	Exon 7 of 9	ENSP00000381170.3	Q6T4R5-3

Frequencies

GnomAD3 genomes AF: 0.286 AC: 31762 AN: 111144 Hom.: 8315 Cov.: 22

Gnomad AFR AF: 0.829

Gnomad AMI AF: 0.00292

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.0578

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.173

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.291

GnomAD2 exomes AF: 0.169 AC: 30921 AN: 183226 AF XY: 0.132

Gnomad AFR exome AF: 0.843

Gnomad AMR exome AF: 0.347

Gnomad ASJ exome AF: 0.0529

Gnomad EAS exome AF: 0.435

Gnomad FIN exome AF: 0.0197

Gnomad NFE exome AF: 0.0253

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.0692 AC: 76037 AN: 1098178 Hom.: 11793 Cov.: 33 AF XY: 0.0629 AC XY: 22883 AN XY: 363536

African (AFR) AF: 0.853 AC: 22510 AN: 26400

American (AMR) AF: 0.343 AC: 12058 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.0545 AC: 1057 AN: 19386

East Asian (EAS) AF: 0.450 AC: 13599 AN: 30205

South Asian (SAS) AF: 0.0496 AC: 2686 AN: 54147

European-Finnish (FIN) AF: 0.0192 AC: 780 AN: 40530

Middle Eastern (MID) AF: 0.161 AC: 665 AN: 4137

European-Non Finnish (NFE) AF: 0.0201 AC: 16943 AN: 842075

Other (OTH) AF: 0.125 AC: 5739 AN: 46094

GnomAD4 genome AF: 0.286 AC: 31835 AN: 111198 Hom.: 8322 Cov.: 22 AF XY: 0.268 AC XY: 8960 AN XY: 33422

African (AFR) AF: 0.829 AC: 25182 AN: 30363

American (AMR) AF: 0.290 AC: 3042 AN: 10487

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 149 AN: 2639

East Asian (EAS) AF: 0.427 AC: 1476 AN: 3459

South Asian (SAS) AF: 0.0583 AC: 156 AN: 2674

European-Finnish (FIN) AF: 0.0200 AC: 121 AN: 6038

Middle Eastern (MID) AF: 0.171 AC: 37 AN: 216

European-Non Finnish (NFE) AF: 0.0229 AC: 1219 AN: 53119

Other (OTH) AF: 0.297 AC: 451 AN: 1519

Alfa AF: 0.141 Hom.: 16058

Bravo AF: 0.339

TwinsUK AF: 0.0267 AC: 99

ALSPAC AF: 0.0239 AC: 69

ESP6500AA AF: 0.815 AC: 3124

ESP6500EA AF: 0.0268 AC: 180

ExAC AF: 0.161 AC: 19584

EpiCase AF: 0.0305

EpiControl AF: 0.0309

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Nance-Horan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.97	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.58
DANN	Benign	0.31
DEOGEN2	Benign	0.0017	T
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	6.1e-7	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.10
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.57	N
REVEL	Benign	0.034
Sift	Benign	1.0	T
Sift4G	Benign	0.66	T
Vest4		0.018
MPC		0.40
ClinPred		0.000012	T
GERP RS		0.69
gMVP		0.13
Mutation Taster		=100/0	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: rs3747295; hg19: chrX-17746244; COSMIC: COSV66275626; COSMIC: COSV66275626;