X-17375820-C-T

Variant names:

• chrX-17375820-C-T
• rs1435156319
• NM_001291867.2:c.63C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_001291867.2(NHS):​c.63C>T​(p.Pro21Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,037,926 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P21P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000087 (0 hom. 5 hem.)
• Consequence: NHS NM_001291867.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.280
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP7: Synonymous conserved (PhyloP=0.28 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 9 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2	c.63C>T	p.Pro21Pro	synonymous_variant	Exon 1 of 9	ENST00000676302.1	NP_001278796.1
NHS	NM_198270.4	c.63C>T	p.Pro21Pro	synonymous_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.63C>T	p.Pro21Pro	synonymous_variant	Exon 1 of 9		NM_001291867.2	ENSP00000502262.1
NHS	ENST00000380060.7	c.63C>T	p.Pro21Pro	synonymous_variant	Exon 1 of 8	1		ENSP00000369400.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000867 AC: 9 AN: 1037926 Hom.: 0 Cov.: 31 AF XY: 0.0000147 AC XY: 5 AN XY: 339070

African (AFR) AF: 0.00 AC: 0 AN: 24653

American (AMR) AF: 0.00 AC: 0 AN: 27755

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18523

East Asian (EAS) AF: 0.0000371 AC: 1 AN: 26971

South Asian (SAS) AF: 0.000121 AC: 6 AN: 49574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25573

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2838

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 817998

Other (OTH) AF: 0.0000227 AC: 1 AN: 44041

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.3
DANN	Benign	0.89
PhyloP100		0.28
PromoterAI		-0.036	Neutral

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: rs1435156319; hg19: chrX-17393943;