1-30933339-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_001020658.2(PUM1):c.3439C>T(p.Arg1147Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: PUM1 NM_001020658.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.12

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PUM1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• PP5: Variant 1-30933339-G-A is Pathogenic according to our data. Variant chr1-30933339-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 617918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PUM1	NM_001020658.2	c.3439C>T	p.Arg1147Trp	missense_variant	22/22	ENST00000426105.7
PUM1	NM_014676.3	c.3433C>T	p.Arg1145Trp	missense_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PUM1	ENST00000426105.7	c.3439C>T	p.Arg1147Trp	missense_variant	22/22	1	NM_001020658.2	A1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia 47 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jun 24, 2020	ACMG codes:PS2; PS3; PS4M; PM2; PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Neurology Department, Shenzhen Children's Hospital	-	Trio-based WES revealed that the exon 22 of the PUM1 gene had a de novo heterozygous missense variant which is otherwise absent in population databases (dbSNP, ExAC, and GnomAD). Thus far, at least three unrelated patients with this variant have been reported (Bonnemason-Carrere et al., 2019; Gennarino et al., 2018; Voet et al., 2020), and all of them were de novo. Upon Western blotting analysis, it was found that the PUM1 protein stability was markedly compromised by this variant (Gennarino et al., 2018). Taken together, according to the American college of medical genetics and genomics guidelines, this variant is considered pathogenic (Richards et al., 2015). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2023	Published functional studies demonstrate a damaging effect (moderately impaired PUM1 repression activity) (Gennarino et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29474920, 34930662, 31859446, 30903679, 35386260) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2018	- -

Neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 21, 2024	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Apr 29, 2024	This variant is interpreted as Likely Pathogenic, for Neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls or at extremely low frequency if recessive in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2_supporting). Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3 ). Confirmed de novo (PS2) (PMID: 29474920, 30903679, 31859446, 35386260). Prevalence in affected individuals statistically increased over controls (PS4_supporting) . Well-established functional studies show a deleterious effect ( PS3_supporting) (https://www.ncbi.nlm.nih.gov/pubmed/29474920). -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2021

The c.3439C>T (p.R1147W) alteration is located in exon 22 (coding exon 21) of the PUM1 gene. This alteration results from a C to T substitution at nucleotide position 3439, causing the arginine (R) at amino acid position 1147 to be replaced by a tryptophan (W). Based on data from the Genome Aggregation Database (gnomAD), the PUM1 c.3439C>T alteration was not observed, with coverage at this position. This alteration has been described to occur de novo in three unrelated individuals who presented with a neurodevelopmental disorder and similar additional features including epilepsy, dysmorphic facial features, hypotonia, cryptorchidism, strabismus, and various brain anomalies on MRI (Bonnemason-Carrere, 2019; Gennarino, 2018; Voet, 2020). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for the p.R1147W alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;D;.;.;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.5	D;D;D;D;D;D;D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;.;D;D;.
Vest4		0.79
MutPred		0.54		.;.;.;.;.;Gain of methylation at K1181 (P = 0.05);.;
MVP		0.70
MPC		2.1
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.83

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

Other links and lift over

dbSNP: rs1557539450; hg19: chr1-31406186; COSMIC: COSV57086710; COSMIC: COSV57086710;