X-17732174-T-C

Position:

• chrX-17732174-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001291867.2(NHS):​c.4666T>C​(p.Ser1556Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000082 in 1,098,186 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. 10/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 4 hem.)
• Consequence: NHS NM_001291867.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.195

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.093857825).
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHS	NM_001291867.2	c.4666T>C	p.Ser1556Pro	missense_variant	9/9	ENST00000676302.1	NP_001278796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1	c.4666T>C	p.Ser1556Pro	missense_variant	9/9		NM_001291867.2	ENSP00000502262.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000820 AC: 9 AN: 1098186 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 4 AN XY: 363540

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000950

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	.;.;T;T
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.56	T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.094	T;T;T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.4	N;N;.;.
REVEL	Benign	0.093
Sift	Benign	0.034	D;T;.;.
Sift4G	Benign	0.098	T;T;T;T
Vest4		0.16
MutPred		0.24		Loss of phosphorylation at S1535 (P = 0.0065);.;.;.;
MVP		0.28
MPC		0.44
ClinPred		0.68	D
GERP RS		-0.063
gMVP		0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs2071848; hg19: chrX-17750294;