rs797045740
Variant summary
Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP3
The ENST00000676302.1(NHS):c.1943_1945dupCCA(p.Thr648dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,098,222 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 22)
Exomes 𝑓: 0.0000027 ( 0 hom. 0 hem. )
Consequence
NHS
ENST00000676302.1 disruptive_inframe_insertion
ENST00000676302.1 disruptive_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.95
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 syndromeInheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
- early-onset nuclear cataractInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in ENST00000676302.1. Strenght limited to Supporting due to length of the change: 1aa.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
Variant Effect in Transcripts
ACMG analysis was done for transcript: ENST00000676302.1. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NHS | NM_001291867.2 | MANE Select | c.1943_1945dupCCA | p.Thr648dup | disruptive_inframe_insertion | Exon 7 of 9 | NP_001278796.1 | ||
| NHS | NM_198270.4 | c.1880_1882dupCCA | p.Thr627dup | disruptive_inframe_insertion | Exon 6 of 8 | NP_938011.1 | |||
| NHS | NM_001440780.1 | c.1604_1606dupCCA | p.Thr535dup | disruptive_inframe_insertion | Exon 7 of 9 | NP_001427709.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NHS | ENST00000676302.1 | MANE Select | c.1943_1945dupCCA | p.Thr648dup | disruptive_inframe_insertion | Exon 7 of 9 | ENSP00000502262.1 | ||
| NHS | ENST00000380060.7 | TSL:1 | c.1880_1882dupCCA | p.Thr627dup | disruptive_inframe_insertion | Exon 6 of 8 | ENSP00000369400.3 | ||
| NHS | ENST00000398097.7 | TSL:1 | c.1412_1414dupCCA | p.Thr471dup | disruptive_inframe_insertion | Exon 7 of 9 | ENSP00000381170.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
22
GnomAD2 exomes AF: 0.00000546 AC: 1AN: 183113 AF XY: 0.00 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
183113
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000273 AC: 3AN: 1098222Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 363576 show subpopulations
GnomAD4 exome
AF:
AC:
3
AN:
1098222
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
363576
show subpopulations
African (AFR)
AF:
AC:
3
AN:
26400
American (AMR)
AF:
AC:
0
AN:
35207
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
19385
East Asian (EAS)
AF:
AC:
0
AN:
30206
South Asian (SAS)
AF:
AC:
0
AN:
54149
European-Finnish (FIN)
AF:
AC:
0
AN:
40530
Middle Eastern (MID)
AF:
AC:
0
AN:
4137
European-Non Finnish (NFE)
AF:
AC:
0
AN:
842111
Other (OTH)
AF:
AC:
0
AN:
46097
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
22
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions as Germline
Significance:Uncertain significance
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
-
1
-
not specified (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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