rs3809724

Positions:

• chr17-58983877-G-A

Variant summary

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

The NM_014906.5(PPM1E):​c.*2846G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 152,488 control chromosomes in the GnomAD database, including 2,356 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2341 hom., cov: 32)
  • Exomes 𝑓: 0.27 (15 hom.)
• Consequence: PPM1E NM_014906.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16

Genes affected

PPM1E (HGNC:19322): (protein phosphatase, Mg2+/Mn2+ dependent 1E) This gene encodes a member of the PPM family of serine/threonine-protein phosphatases. The encoded protein is localized to the nucleus and dephosphorylates and inactivates multiple substrates including serine/threonine-protein kinase PAK 1, 5'-AMP-activated protein kinase (AMPK) and the multifunctional calcium/calmodulin-dependent protein kinases. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, May 2012]

TRIM37 (HGNC:7523): (tripartite motif containing 37) This gene encodes a member of the tripartite motif (TRIM) family, whose members are involved in diverse cellular functions such as developmental patterning and oncogenesis. The TRIM motif includes zinc-binding domains, a RING finger region, a B-box motif and a coiled-coil domain. The RING finger and B-box domains chelate zinc and might be involved in protein-protein and/or protein-nucleic acid interactions. Mutations in this gene are associated with mulibrey (muscle-liver-brain-eye) nanism, an autosomal recessive disorder that involves several tissues of mesodermal origin. TRIM37 localizes in peroxisomal membranes, and has been implicated in human peroxisomal biogenesis disorders. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPM1E	NM_014906.5	c.*2846G>A		3_prime_UTR_variant	7/7	ENST00000308249.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPM1E	ENST00000308249.4	c.*2846G>A		3_prime_UTR_variant	7/7	1	NM_014906.5	P1
TRIM37	ENST00000393066.7	c.2892-956C>T		intron_variant		1		P1
TRIM37	ENST00000583945.5	c.160-956C>T		intron_variant		3
TRIM37	ENST00000585287.5	c.351-956C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24257 AN: 151938 Hom.: 2340 Cov.: 32

Gnomad AFR AF: 0.0556

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.0819

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.0764

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.149

GnomAD4 exome AF: 0.273 AC: 118 AN: 432 Hom.: 15 Cov.: 0 AF XY: 0.269 AC XY: 70 AN XY: 260

Gnomad4 FIN exome AF: 0.275

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.160 AC: 24270 AN: 152056 Hom.: 2341 Cov.: 32 AF XY: 0.163 AC XY: 12088 AN XY: 74296

Gnomad4 AFR AF: 0.0556

Gnomad4 AMR AF: 0.165

Gnomad4 ASJ AF: 0.0819

Gnomad4 EAS AF: 0.180

Gnomad4 SAS AF: 0.136

Gnomad4 FIN AF: 0.263

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.147

Alfa AF: 0.185 Hom.: 3624

Bravo AF: 0.143

Asia WGS AF: 0.158 AC: 549 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.5
DANN	Benign	0.56

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: rs3809724; hg19: chr17-57061238; COSMIC: COSV57574582;