rs756026847

Variant names:

• chr2-121530916-G-A
• rs756026847
• ENST00000580972.2:n.37G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-121530916-G-A
• chr2-121530916-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BP4

The ENST00000580972.2(RNU4ATAC):​n.37G>A variant causes a non coding transcript exon change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000901 in 699,402 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: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000091 (0 hom.)
• Consequence: RNU4ATAC ENST00000580972.2 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:2
• Conservation: PhyloP100: 9.43
• Publications: 2 publications found

Genes affected

RNU4ATAC (HGNC:34016): (RNA, U4atac small nuclear) The small nuclear RNA (snRNA) encoded by this gene is part of the U12-dependent minor spliceosome complex. In addition to the encoded RNA, this ribonucleoprotein complex consists of U11, U12, U5, and U6atac snRNAs. The U12-dependent spliceosome acts on approximately 700 specific introns in the human genome. Defects in this gene are a cause of microcephalic osteodysplastic primordial dwarfism type 1 (MOPD). [provided by RefSeq, Jul 2011]

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]

CLASP1-AS1 (HGNC:55328): (CLASP1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP5: Variant 2-121530916-G-A is Pathogenic according to our data. Variant chr2-121530916-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218084.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000580972.2. 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
	RNU4ATAC	NR_023343.3	MANE Select	n.37G>A		non_coding_transcript_exon	Exon 1 of 1
	CLASP1	NM_001395891.1	MANE Select	c.196-591C>T		intron	N/A	NP_001382820.1
	CLASP1	NM_015282.3		c.196-591C>T		intron	N/A	NP_056097.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNU4ATAC	ENST00000580972.2	TSL:6 MANE Select	n.37G>A		non_coding_transcript_exon	Exon 1 of 1
	CLASP1	ENST00000696935.1	MANE Select	c.196-591C>T		intron	N/A	ENSP00000512981.1
	CLASP1	ENST00000263710.8	TSL:5	c.196-591C>T		intron	N/A	ENSP00000263710.4

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000613 AC: 8 AN: 130446 AF XY: 0.0000702

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000121

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000914 AC: 50 AN: 547192 Hom.: 0 Cov.: 0 AF XY: 0.0000945 AC XY: 28 AN XY: 296150

African (AFR) AF: 0.0000636 AC: 1 AN: 15720

American (AMR) AF: 0.00 AC: 0 AN: 34696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20006

East Asian (EAS) AF: 0.0000312 AC: 1 AN: 32068

South Asian (SAS) AF: 0.0000319 AC: 2 AN: 62648

European-Finnish (FIN) AF: 0.0000904 AC: 3 AN: 33190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2440

European-Non Finnish (NFE) AF: 0.000136 AC: 43 AN: 316048

Other (OTH) AF: 0.00 AC: 0 AN: 30376

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74358

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000831

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Roifman syndrome (3)
-	1	-	CLASP1-related disorder (1)
1	-	-	Lowry-Wood syndrome;C1846059:Roifman syndrome;C1859452:Osteodysplastic primordial dwarfism, type 1 (1)
1	-	-	not provided (1)
1	-	-	Osteodysplastic primordial dwarfism, type 1 (1)
1	-	-	RNU4ATAC-related disorder (1)
1	-	-	Spondyloepiphyseal dysplasia congenita (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Benign	0.95
PhyloP100		9.4
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs756026847; hg19: chr2-122288492;