1-30936787-A-G

Variant names:

• chr1-30936787-A-G
• rs56143291
• NM_001020658.2:c.3291T>C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001020658.2(PUM1):​c.3291T>C​(p.Ala1097Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,613,962 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (3 hom., cov: 30)
  • Exomes 𝑓: 0.0031 (9 hom.)
• Consequence: PUM1 NM_001020658.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.827

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 1-30936787-A-G is Benign according to our data. Variant chr1-30936787-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2638593.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.827 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00194 (295/152330) while in subpopulation NFE AF= 0.00322 (219/68034). AF 95% confidence interval is 0.00287. There are 3 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 295 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PUM1	NM_001020658.2	c.3291T>C	p.Ala1097Ala	synonymous_variant	Exon 21 of 22	ENST00000426105.7	NP_001018494.1
PUM1	NM_014676.3	c.3285T>C	p.Ala1095Ala	synonymous_variant	Exon 21 of 22		NP_055491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PUM1	ENST00000426105.7	c.3291T>C	p.Ala1097Ala	synonymous_variant	Exon 21 of 22	1	NM_001020658.2	ENSP00000391723.2

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 293 AN: 152212 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00226 AC: 567 AN: 250854 Hom.: 4 AF XY: 0.00232 AC XY: 315 AN XY: 135504

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.00277

Gnomad NFE exome AF: 0.00334

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00306 AC: 4470 AN: 1461632 Hom.: 9 Cov.: 31 AF XY: 0.00301 AC XY: 2187 AN XY: 727134

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00180

Gnomad4 FIN exome AF: 0.00266

Gnomad4 NFE exome AF: 0.00345

Gnomad4 OTH exome AF: 0.00291

GnomAD4 genome AF: 0.00194 AC: 295 AN: 152330 Hom.: 3 Cov.: 30 AF XY: 0.00177 AC XY: 132 AN XY: 74486

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00322

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00326 Hom.: 0

Bravo AF: 0.00189

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00326

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PUM1: BP4, BP7 -

PUM1-related disorder Benign:1

Feb 19, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.4
DANN	Benign	0.61

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: rs56143291; hg19: chr1-31409634;