rs727504039

Variant names:

• chrX-17375909-C-G
• rs727504039
• NM_001291867.2:c.152C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-17375909-C-G
• chrX-17375909-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001291867.2(NHS):​c.152C>G​(p.Ala51Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 983,242 control chromosomes in the GnomAD database, including 1 homozygotes. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A51V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000013 (1 hom. 7 hem.)
• Consequence: NHS NM_001291867.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.309
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005764991).
• BS2: High AC in GnomAdExome4 at 13 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2	c.152C>G	p.Ala51Gly	missense_variant	Exon 1 of 9	ENST00000676302.1	NP_001278796.1
NHS	NM_198270.4	c.152C>G	p.Ala51Gly	missense_variant	Exon 1 of 8		NP_938011.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1	c.152C>G	p.Ala51Gly	missense_variant	Exon 1 of 9		NM_001291867.2	ENSP00000502262.1
NHS	ENST00000380060.7	c.152C>G	p.Ala51Gly	missense_variant	Exon 1 of 8	1		ENSP00000369400.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000220 AC: 1 AN: 45459 AF XY: 0.0000782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000132 AC: 13 AN: 983242 Hom.: 1 Cov.: 32 AF XY: 0.0000222 AC XY: 7 AN XY: 315438

African (AFR) AF: 0.00 AC: 0 AN: 20584

American (AMR) AF: 0.00 AC: 0 AN: 19393

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15917

East Asian (EAS) AF: 0.00 AC: 0 AN: 22519

South Asian (SAS) AF: 0.000259 AC: 11 AN: 42449

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24761

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2649

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 793685

Other (OTH) AF: 0.0000484 AC: 2 AN: 41285

GnomAD4 genome Cov.: 23

ExAC AF: 0.000152 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	12
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.31
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.030
Sift	Benign	0.36	T
Sift4G	Benign	0.090	T
Vest4		0.054
MutPred		0.23		Gain of relative solvent accessibility (P = 0.005);
MVP		0.48
MPC		0.38
ClinPred		0.050	T
GERP RS		1.4
PromoterAI		-0.020	Neutral
gMVP		0.034
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: rs727504039; hg19: chrX-17394032;