rs181195449

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5BP4BS2_Supporting

The NM_001395891.1(CLASP1):​c.196-604C>T variant causes a intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 700,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: đť‘“ 0.00018 ( 0 hom., cov: 33)
Exomes đť‘“: 0.00016 ( 0 hom. )

Consequence

CLASP1
NM_001395891.1 intron

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 7.57
Variant links:
Genes affected
CLASP1 (HGNC:17088): (cytoplasmic linker associated protein 1) CLASPs, such as CLASP1, are nonmotor microtubule-associated proteins that interact with CLIPs (e.g., CLIP170; MIM 179838). CLASP1 is involved in the regulation of microtubule dynamics at the kinetochore and throughout the spindle (Maiato et al., 2003 [PubMed 12837247]).[supplied by OMIM, Mar 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP5
Variant 2-121530929-G-A is Pathogenic according to our data. Variant chr2-121530929-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 30184.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3}. Variant chr2-121530929-G-A is described in Lovd as [Pathogenic]. Variant chr2-121530929-G-A is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.27). . Strength limited to SUPPORTING due to the PP5.
BS2
High AC in GnomAd4 at 27 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CLASP1NM_001395891.1 linkuse as main transcriptc.196-604C>T intron_variant ENST00000696935.1 NP_001382820.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CLASP1ENST00000696935.1 linkuse as main transcriptc.196-604C>T intron_variant NM_001395891.1 ENSP00000512981.1 A0A8V8TLP7

Frequencies

GnomAD3 genomes
AF:
0.000177
AC:
27
AN:
152180
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000123
AC:
16
AN:
130504
Hom.:
0
AF XY:
0.0000983
AC XY:
7
AN XY:
71228
show subpopulations
Gnomad AFR exome
AF:
0.000164
Gnomad AMR exome
AF:
0.000123
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000192
Gnomad SAS exome
AF:
0.0000447
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000181
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000164
AC:
90
AN:
548048
Hom.:
0
Cov.:
0
AF XY:
0.000135
AC XY:
40
AN XY:
296756
show subpopulations
Gnomad4 AFR exome
AF:
0.000191
Gnomad4 AMR exome
AF:
0.000231
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000218
Gnomad4 SAS exome
AF:
0.0000638
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000199
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
AF:
0.000177
AC:
27
AN:
152180
Hom.:
0
Cov.:
33
AF XY:
0.000148
AC XY:
11
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000108
Hom.:
0
Bravo
AF:
0.000212

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 09, 2022This variant occurs in the RNU4ATAC gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (rs181195449, gnomAD 0.02%). This variant has been observed in individuals with autosomal recessive RNU4ATAC-related conditions (PMID: 21474761, 33059947). This variant is also known as g.50G>A. ClinVar contains an entry for this variant (Variation ID: 30184). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant is located within the 5' stem-loop region of the RNU4ATAC RNA, which includes the 15.5K binding site and is important for spliceosome assembly (PMID: 32628740). A significant number of disease-associated RNU4ATAC variants are found in this region (PMID: 32628740, 30368667). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsNov 30, 2019- -
Likely pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJun 25, 2021The non-coding variant, n.50G>A, has been described in gnomAD with an allele frequency of 0.021% in the Non-Finnish European sub-population (dbSNP rsrs181195449). This sequence change is located in the 5' stem loop critical region, a region important for splicing (PMID:32628740). The n.50G>A has previously been observed in the compound heterozygous state with the n.51G>A pathogenic sequence change in an individual with intrauterine growth retardation, microcephaly, agenesis of the corpus callosum, and polymicrogyria (PMID: 21474761). Based on this information this variant is being classified as likely pathogenic. -
Roifman syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMay 06, 2021Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microcephalic osteodysplastic primordial dwarfism, type I (MOPD1) (MIM# 210710) and Roifman syndrome (MIM# 616651). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0218 - Non-coding variant without predicted effect on gene expression of downstream targets. This small nuclear RNA forms part of a spliceosome essential for minor intron splicing (PMID: 26522830). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 27 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same position is present in gnomAD (v2: 3 heterozygotes, 0 homozygotes). (I) 0601 - Variant is located in the well-established functional 5' stem-loop structure (PMID: 26522830). (SP) 0704 - Another variant comparable to the one identified in this case has limited previous evidence for pathogenicity. n.50G>C was identified in a MOPD1 patient who was compound heterozygous with n.51G>A (PMID: 21474761). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. It was identified in a MOPD1 patient who was compound heterozygous with n.51G>A (PMID: 21474761). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria providedclinical testingUndiagnosed Diseases Network, NIHJan 05, 2024- -
Osteodysplastic primordial dwarfism, type 1 Pathogenic:2
Pathogenic, no assertion criteria providedclinical testingService de Génétique Moléculaire, Hôpital Robert Debré-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 08, 2011- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.27
CADD
Benign
19
DANN
Benign
0.92
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs181195449; hg19: chr2-122288505; API