1-30942015-T-A

Position:

• chr1-30942015-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2 PP2 PP5_Very_Strong BP4

The NM_001020658.2(PUM1):​c.3103A>T​(p.Thr1035Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000021 in 1,430,084 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PUM1 NM_001020658.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.17

Genes affected

PUM1 (HGNC:14957): (pumilio RNA binding family member 1) This gene encodes a member of the PUF family, evolutionarily conserved RNA-binding proteins related to the Pumilio proteins of Drosophila and the fem-3 mRNA binding factor proteins of C. elegans. The encoded protein contains a sequence-specific RNA binding domain comprised of eight repeats and N- and C-terminal flanking regions, and serves as a translational regulator of specific mRNAs by binding to their 3' untranslated regions. The evolutionarily conserved function of the encoded protein in invertebrates and lower vertebrates suggests that the human protein may be involved in translational regulation of embryogenesis, and cell development and differentiation. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PUM1
• PP5: Variant 1-30942015-T-A is Pathogenic according to our data. Variant chr1-30942015-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 617924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.35756022). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PUM1	NM_001020658.2	c.3103A>T	p.Thr1035Ser	missense_variant	19/22	ENST00000426105.7
PUM1	NM_014676.3	c.3097A>T	p.Thr1033Ser	missense_variant	19/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PUM1	ENST00000426105.7	c.3103A>T	p.Thr1035Ser	missense_variant	19/22	1	NM_001020658.2	A1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251328 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135832

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1430084 Hom.: 0 Cov.: 30 AF XY: 0.00000421 AC XY: 3 AN XY: 711922

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000275

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia 47 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 27, 2021	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	This variant is interpreted as Likely Pathogenic, for Spinocerebellar ataxia 47, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/29474920). PS3 => Well-established functional studies show a deleterious effect PUM1 (https://www.ncbi.nlm.nih.gov/pubmed/29474920). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 15, 2021

Published functional studies suggest a damaging effect: inability to suppress ATNX1 and E2F3 (Gennarino et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30284037, 30316580, 33397688, 33163565, 29474920) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.078	T;T;.;.;.;.;.
Eigen	Benign	0.095
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.36	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D;D
REVEL	Benign	0.14
Sift	Benign	0.17	T;T;T;T;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T;T;T
Polyphen		0.0030, 0.11, 0.0010	.;B;B;.;B;B;.
Vest4		0.53
MutPred		0.56		.;.;.;.;.;Gain of disorder (P = 0.0572);.;
MVP		0.33
MPC		0.93
ClinPred		0.71	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs771145682; hg19: chr1-31414862;