rs111759069

chr15-23646664-G-Achr15-23646664-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_019066.5(MAGEL2):c.1079C>T(p.Ala360Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0098 in 1,504,542 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A360A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0069 (7 hom., cov: 33)
  • Exomes 𝑓: 0.010 (107 hom.)
• Consequence: MAGEL2 NM_019066.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.469

Genes affected

MAGEL2 (HGNC:6814): (MAGE family member L2) Prader-Willi syndrome (PWS) is caused by the loss of expression of imprinted genes in chromosome 15q11-q13 region. Affected individuals exhibit neonatal hypotonia, developmental delay, and childhood-onset obesity. Necdin (NDN), a gene involved in the terminal differentiation of neurons, localizes to this region of the genome and has been implicated as one of the genes responsible for the etiology of PWS. This gene is structurally similar to NDN, is also localized to the PWS chromosomal region, and is paternally imprinted, suggesting a possible role for it in PWS. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054139197).
• BP6: Variant 15-23646664-G-A is Benign according to our data. Variant chr15-23646664-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 193398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-23646664-G-A is described in Lovd as [Benign]. Variant chr15-23646664-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00691 (1052/152188) while in subpopulation NFE AF= 0.0125 (850/67982). AF 95% confidence interval is 0.0118. There are 7 homozygotes in gnomad4. There are 453 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1053 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGEL2	NM_019066.5	c.1079C>T	p.Ala360Val	missense_variant	1/1	ENST00000650528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGEL2	ENST00000650528.1	c.1079C>T	p.Ala360Val	missense_variant	1/1		NM_019066.5	P1

Frequencies

GnomAD3 genomes AF: 0.00692 AC: 1053 AN: 152070 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00570 AC: 642 AN: 112578 Hom.: 3 AF XY: 0.00581 AC XY: 346 AN XY: 59508

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.000176

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000239

Gnomad FIN exome AF: 0.00467

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.00496

GnomAD4 exome AF: 0.0101 AC: 13691 AN: 1352354 Hom.: 107 Cov.: 32 AF XY: 0.00986 AC XY: 6540 AN XY: 663390

Gnomad4 AFR exome AF: 0.00181

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.000220

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000355

Gnomad4 FIN exome AF: 0.00446

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.00659

GnomAD4 genome AF: 0.00691 AC: 1052 AN: 152188 Hom.: 7 Cov.: 33 AF XY: 0.00609 AC XY: 453 AN XY: 74386

Gnomad4 AFR AF: 0.00248

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00484 Hom.: 2

Bravo AF: 0.00663

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0130 AC: 50

ExAC AF: 0.00128 AC: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MAGEL2: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 13, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	17
Dann	Benign	0.82
DEOGEN2	Benign	0.038	T;T
FATHMM_MKL	Benign	0.038	N
MetaRNN	Benign	0.0054	T;T
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.1	N;.
Sift	Uncertain	0.019	D;.
Sift4G	Benign	0.32	T;.
Vest4		0.12
MVP		0.14
GERP RS		2.1
Varity_R		0.030
gMVP		0.058

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: rs111759069; hg19: chr15-23891811;