rs2270891

Positions:

• chr9-2828742-C-A
• chr9-2828742-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000397885.3(PUM3):​c.889G>T​(p.Val297Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0378 in 1,605,370 control chromosomes in the GnomAD database, including 1,348 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.043 (152 hom., cov: 33)
  • Exomes 𝑓: 0.037 (1196 hom.)
• Consequence: PUM3 ENST00000397885.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.734

Genes affected

PUM3 (HGNC:29676): (pumilio RNA binding family member 3) Enables RNA binding activity. Involved in regulation of protein ADP-ribosylation. Located in chromosome; endoplasmic reticulum; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017007887).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PUM3	NM_014878.5	c.889G>T	p.Val297Leu	missense_variant	9/18	ENST00000397885.3	NP_055693.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PUM3	ENST00000397885.3	c.889G>T	p.Val297Leu	missense_variant	9/18	1	NM_014878.5	ENSP00000380982	P1
PUM3	ENST00000469168.1	n.189G>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0426 AC: 6488 AN: 152154 Hom.: 152 Cov.: 33

Gnomad AFR AF: 0.0516

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0406

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.0712

Gnomad SAS AF: 0.0340

Gnomad FIN AF: 0.0383

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0370

Gnomad OTH AF: 0.0435

GnomAD3 exomes AF: 0.0426 AC: 10687 AN: 250982 Hom.: 241 AF XY: 0.0411 AC XY: 5578 AN XY: 135652

Gnomad AFR exome AF: 0.0512

Gnomad AMR exome AF: 0.0557

Gnomad ASJ exome AF: 0.0387

Gnomad EAS exome AF: 0.0604

Gnomad SAS exome AF: 0.0377

Gnomad FIN exome AF: 0.0402

Gnomad NFE exome AF: 0.0365

Gnomad OTH exome AF: 0.0435

GnomAD4 exome AF: 0.0373 AC: 54180 AN: 1453098 Hom.: 1196 Cov.: 28 AF XY: 0.0373 AC XY: 26982 AN XY: 723512

Gnomad4 AFR exome AF: 0.0474

Gnomad4 AMR exome AF: 0.0548

Gnomad4 ASJ exome AF: 0.0379

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.0355

Gnomad4 FIN exome AF: 0.0402

Gnomad4 NFE exome AF: 0.0339

Gnomad4 OTH exome AF: 0.0375

GnomAD4 genome AF: 0.0426 AC: 6491 AN: 152272 Hom.: 152 Cov.: 33 AF XY: 0.0420 AC XY: 3128 AN XY: 74456

Gnomad4 AFR AF: 0.0514

Gnomad4 AMR AF: 0.0406

Gnomad4 ASJ AF: 0.0383

Gnomad4 EAS AF: 0.0713

Gnomad4 SAS AF: 0.0340

Gnomad4 FIN AF: 0.0383

Gnomad4 NFE AF: 0.0370

Gnomad4 OTH AF: 0.0435

Alfa AF: 0.0376 Hom.: 208

Bravo AF: 0.0439

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0317 AC: 122

ESP6500AA AF: 0.0495 AC: 218

ESP6500EA AF: 0.0397 AC: 341

ExAC AF: 0.0431 AC: 5231

Asia WGS AF: 0.0600 AC: 210 AN: 3478

EpiCase AF: 0.0384

EpiControl AF: 0.0366

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	8.1
DANN	Benign	0.96
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.060
Sift	Benign	0.34	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.030
MutPred		0.097		Loss of ubiquitination at K293 (P = 0.0834);
MPC		0.0035
ClinPred		0.0013	T
GERP RS		0.67
Varity_R		0.075
gMVP		0.39

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: rs2270891; hg19: chr9-2828742; COSMIC: COSV67396424;