NM_001291867.2:c.348_350delGGC

Variant names:

• chrX-17376088-TCGG-T
• rs587780401
• NM_001291867.2:c.348_350delGGC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001291867.2(NHS):​c.348_350delGGC​(p.Ala117del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,074,393 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.00016 (0 hom. 3 hem.)
• Consequence: NHS NM_001291867.2 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.51
• 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Ambry Genetics
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001291867.2

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.348_350delGGC	p.Ala117del	disruptive_inframe_deletion	Exon 1 of 9	NP_001278796.1	Q6T4R5-1
	NHS	NM_198270.4		c.348_350delGGC	p.Ala117del	disruptive_inframe_deletion	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.348_350delGGC	p.Ala117del	disruptive_inframe_deletion	Exon 1 of 9	ENSP00000502262.1	Q6T4R5-1
	NHS	ENST00000380060.7	TSL:1	c.348_350delGGC	p.Ala117del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000369400.3	Q6T4R5-2

Frequencies

GnomAD3 genomes AF: 0.0000181 AC: 2 AN: 110363 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000188

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00200 AC: 65 AN: 32481 AF XY: 0.000129

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00114

Gnomad EAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00128

Gnomad NFE exome AF: 0.00213

Gnomad OTH exome AF: 0.00398

GnomAD4 exome AF: 0.000159 AC: 153 AN: 964030 Hom.: 0 AF XY: 0.00000984 AC XY: 3 AN XY: 304798

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000147 AC: 3 AN: 20340

American (AMR) AF: 0.00121 AC: 20 AN: 16492

Ashkenazi Jewish (ASJ) AF: 0.000449 AC: 7 AN: 15606

East Asian (EAS) AF: 0.000181 AC: 4 AN: 22083

South Asian (SAS) AF: 0.000491 AC: 19 AN: 38700

European-Finnish (FIN) AF: 0.0000412 AC: 1 AN: 24287

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2689

European-Non Finnish (NFE) AF: 0.000115 AC: 90 AN: 783308

Other (OTH) AF: 0.000222 AC: 9 AN: 40525

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000181 AC: 2 AN: 110363 Hom.: 0 Cov.: 23 AF XY: 0.0000300 AC XY: 1 AN XY: 33335

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30339

American (AMR) AF: 0.000188 AC: 2 AN: 10615

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2620

East Asian (EAS) AF: 0.00 AC: 0 AN: 3428

South Asian (SAS) AF: 0.00 AC: 0 AN: 2676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5827

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52472

Other (OTH) AF: 0.00 AC: 0 AN: 1475

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Nance-Horan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5
Mutation Taster		=82/18	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: rs587780401; hg19: chrX-17394211;