X-17376270-C-G

Variant names:

• chrX-17376270-C-G
• rs398124610
• NM_001291867.2:c.513C>G

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.513C>G​(p.Leu171Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000636 in 1,164,143 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 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. L171L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000068 (0 hom. 31 hem.)
• Consequence: NHS NM_001291867.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0610
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• 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=-0.52).
• BP7: Synonymous conserved (PhyloP=-0.061 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 72 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.513C>G	p.Leu171Leu	synonymous	Exon 1 of 9	NP_001278796.1	Q6T4R5-1
	NHS	NM_198270.4		c.513C>G	p.Leu171Leu	synonymous	Exon 1 of 8	NP_938011.1	Q6T4R5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHS	ENST00000676302.1	MANE Select	c.513C>G	p.Leu171Leu	synonymous	Exon 1 of 9	ENSP00000502262.1	Q6T4R5-1
	NHS	ENST00000380060.7	TSL:1	c.513C>G	p.Leu171Leu	synonymous	Exon 1 of 8	ENSP00000369400.3	Q6T4R5-2

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 112043 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000378 AC: 4 AN: 105748 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000722

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000684 AC: 72 AN: 1052100 Hom.: 0 Cov.: 32 AF XY: 0.0000907 AC XY: 31 AN XY: 341730

African (AFR) AF: 0.00 AC: 0 AN: 25503

American (AMR) AF: 0.00 AC: 0 AN: 30301

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18763

East Asian (EAS) AF: 0.00 AC: 0 AN: 28126

South Asian (SAS) AF: 0.00 AC: 0 AN: 50410

European-Finnish (FIN) AF: 0.0000382 AC: 1 AN: 26182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3981

European-Non Finnish (NFE) AF: 0.0000801 AC: 66 AN: 824214

Other (OTH) AF: 0.000112 AC: 5 AN: 44620

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 112043 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34251

African (AFR) AF: 0.0000324 AC: 1 AN: 30886

American (AMR) AF: 0.00 AC: 0 AN: 10754

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3510

South Asian (SAS) AF: 0.00 AC: 0 AN: 2729

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6099

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52995

Other (OTH) AF: 0.00 AC: 0 AN: 1509

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.1
DANN	Benign	0.88
PhyloP100		-0.061

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: rs398124610; hg19: chrX-17394393;