1-30936792-G-A

Position:

• chr1-30936792-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001020658.2(PUM1):​c.3286C>T​(p.Arg1096Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PUM1 NM_001020658.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PUM1	NM_001020658.2	c.3286C>T	p.Arg1096Cys	missense_variant	21/22	ENST00000426105.7	NP_001018494.1
PUM1	NM_014676.3	c.3280C>T	p.Arg1094Cys	missense_variant	21/22		NP_055491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PUM1	ENST00000426105.7	c.3286C>T	p.Arg1096Cys	missense_variant	21/22	1	NM_001020658.2	ENSP00000391723.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461310 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726964

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 05, 2022

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 (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;D;.;.;.;.;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Pathogenic	3.8	.;H;.;.;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.6	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D;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		0.84
MutPred		0.69		.;.;.;.;.;Gain of loop (P = 0.0502);.;.;
MVP		0.76
MPC		2.5
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.95

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: rs1639226110; hg19: chr1-31409639; COSMIC: COSV57086129;