rs769860109

Variant names:

• chrX-17376260-A-G
• rs769860109
• NM_001291867.2:c.503A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001291867.2(NHS):​c.503A>G​(p.Gln168Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000094 in 1,169,623 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.0000085 (0 hom. 4 hem.)
• Consequence: NHS NM_001291867.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.84
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27755043).
• BS2: High AC in GnomAdExome4 at 9 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.503A>G	p.Gln168Arg	missense	Exon 1 of 9	NP_001278796.1
	NHS	NM_198270.4		c.503A>G	p.Gln168Arg	missense	Exon 1 of 8	NP_938011.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHS	ENST00000676302.1	MANE Select	c.503A>G	p.Gln168Arg	missense	Exon 1 of 9	ENSP00000502262.1
	NHS	ENST00000380060.7	TSL:1	c.503A>G	p.Gln168Arg	missense	Exon 1 of 8	ENSP00000369400.3

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111936 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000930

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: 0.0000264 AC: 3 AN: 113556 AF XY: 0.0000276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000135

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: 0.00000851 AC: 9 AN: 1057687 Hom.: 0 Cov.: 32 AF XY: 0.0000116 AC XY: 4 AN XY: 343447

African (AFR) AF: 0.00 AC: 0 AN: 25742

American (AMR) AF: 0.000128 AC: 4 AN: 31329

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18843

East Asian (EAS) AF: 0.00 AC: 0 AN: 28528

South Asian (SAS) AF: 0.00 AC: 0 AN: 50763

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4013

European-Non Finnish (NFE) AF: 0.00000605 AC: 5 AN: 827121

Other (OTH) AF: 0.00 AC: 0 AN: 44848

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111936 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34182

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30898

American (AMR) AF: 0.0000930 AC: 1 AN: 10756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 2707

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6077

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52943

Other (OTH) AF: 0.00 AC: 0 AN: 1505

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000918 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Benign	0.94
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.20
Sift	Benign	0.18	T
Sift4G	Benign	0.84	T
Vest4		0.43
MutPred		0.45		Gain of MoRF binding (P = 0.0432)
MVP		0.45
MPC		0.44
ClinPred		0.28	T
GERP RS		3.9
gMVP		0.66
Mutation Taster		=94/6	polymorphism

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: rs769860109; hg19: chrX-17394383;