X-17375203-G-A

Variant names:

• chrX-17375203-G-A
• rs62586064
• NM_001291867.2:c.-555G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001291867.2(NHS):​c.-555G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 111,683 control chromosomes in the GnomAD database, including 28 homozygotes. There are 711 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.022 (28 hom., 711 hem., cov: 23)
• Consequence: NHS NM_001291867.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.59
• 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: 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-17375203-G-A is Benign according to our data. Variant chrX-17375203-G-A is described in ClinVar as [Benign]. Clinvar id is 1275467.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0221 (2467/111683) while in subpopulation NFE AF = 0.0327 (1726/52860). AF 95% confidence interval is 0.0314. There are 28 homozygotes in GnomAd4. There are 711 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2467 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2	c.-555G>A		5_prime_UTR_variant	Exon 1 of 9	ENST00000676302.1	NP_001278796.1
NHS	NM_198270.4	c.-555G>A		5_prime_UTR_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.-555G>A		5_prime_UTR_variant	Exon 1 of 9		NM_001291867.2	ENSP00000502262.1
NHS	ENST00000380060.7	c.-555G>A		upstream_gene_variant		1		ENSP00000369400.3

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 2467 AN: 111636 Hom.: 28 Cov.: 23

Gnomad AFR AF: 0.00368

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0119

Gnomad FIN AF: 0.0551

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.0326

Gnomad OTH AF: 0.0207

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0221 AC: 2467 AN: 111683 Hom.: 28 Cov.: 23 AF XY: 0.0210 AC XY: 711 AN XY: 33913

African (AFR) AF: 0.00367 AC: 113 AN: 30790

American (AMR) AF: 0.0122 AC: 131 AN: 10746

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 96 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3494

South Asian (SAS) AF: 0.0119 AC: 32 AN: 2690

European-Finnish (FIN) AF: 0.0551 AC: 333 AN: 6049

Middle Eastern (MID) AF: 0.0231 AC: 5 AN: 216

European-Non Finnish (NFE) AF: 0.0327 AC: 1726 AN: 52860

Other (OTH) AF: 0.0204 AC: 31 AN: 1520

Alfa AF: 0.0277 Hom.: 152

Bravo AF: 0.0188

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.97
PhyloP100		1.6
PromoterAI		0.15	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs62586064; hg19: chrX-17393326;