rs398124605

Variant names:

• chrX-17375968-C-T
• rs398124605
• NM_001291867.2:c.211C>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.211C>T​(p.Pro71Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00557 in 1,074,258 control chromosomes in the GnomAD database, including 215 homozygotes. There are 1,592 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (119 hom., 863 hem., cov: 23)
  • Exomes 𝑓: 0.0029 (96 hom. 729 hem.)
• Consequence: NHS NM_001291867.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.642
• Publications: 1 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.001693666).
• BP6: Variant X-17375968-C-T is Benign according to our data. Variant chrX-17375968-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0962 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.211C>T	p.Pro71Ser	missense	Exon 1 of 9	NP_001278796.1	Q6T4R5-1
	NHS	NM_198270.4		c.211C>T	p.Pro71Ser	missense	Exon 1 of 8	NP_938011.1	Q6T4R5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHS	ENST00000676302.1	MANE Select	c.211C>T	p.Pro71Ser	missense	Exon 1 of 9	ENSP00000502262.1	Q6T4R5-1
	NHS	ENST00000380060.7	TSL:1	c.211C>T	p.Pro71Ser	missense	Exon 1 of 8	ENSP00000369400.3	Q6T4R5-2

Frequencies

GnomAD3 genomes AF: 0.0287 AC: 3196 AN: 111221 Hom.: 119 Cov.: 23

Gnomad AFR AF: 0.0992

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.000417

Gnomad OTH AF: 0.0216

GnomAD2 exomes AF: 0.00280 AC: 143 AN: 51037 AF XY: 0.00169

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.00460

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00290 AC: 2788 AN: 962991 Hom.: 96 Cov.: 31 AF XY: 0.00237 AC XY: 729 AN XY: 308143

African (AFR) AF: 0.102 AC: 2093 AN: 20544

American (AMR) AF: 0.00654 AC: 128 AN: 19575

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16048

East Asian (EAS) AF: 0.00 AC: 0 AN: 20182

South Asian (SAS) AF: 0.000392 AC: 16 AN: 40785

European-Finnish (FIN) AF: 0.0000837 AC: 2 AN: 23882

Middle Eastern (MID) AF: 0.00312 AC: 8 AN: 2568

European-Non Finnish (NFE) AF: 0.000299 AC: 233 AN: 779458

Other (OTH) AF: 0.00771 AC: 308 AN: 39949

GnomAD4 genome AF: 0.0288 AC: 3200 AN: 111267 Hom.: 119 Cov.: 23 AF XY: 0.0255 AC XY: 863 AN XY: 33839

African (AFR) AF: 0.0991 AC: 3046 AN: 30729

American (AMR) AF: 0.00916 AC: 98 AN: 10697

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2630

East Asian (EAS) AF: 0.00 AC: 0 AN: 3473

South Asian (SAS) AF: 0.000368 AC: 1 AN: 2716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5857

Middle Eastern (MID) AF: 0.00465 AC: 1 AN: 215

European-Non Finnish (NFE) AF: 0.000417 AC: 22 AN: 52769

Other (OTH) AF: 0.0213 AC: 32 AN: 1500

Alfa AF: 0.0155 Hom.: 69

ExAC AF: 0.00121 AC: 18

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	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	0.086
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.1
DANN	Benign	0.97
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.64
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.026
Sift	Benign	0.48	T
Sift4G	Benign	1.0	T
Vest4		0.20
MVP		0.13
MPC		0.35
ClinPred		0.0078	T
GERP RS		0.21
gMVP		0.085
Mutation Taster		=98/2	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: rs398124605; hg19: chrX-17394091;