15-23643744-A-T

Position:

• chr15-23643744-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019066.5(MAGEL2):​c.*249T>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 0.626 in 402,118 control chromosomes in the GnomAD database, including 82,253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (36244 hom., cov: 33)
  • Exomes 𝑓: 0.60 (46009 hom.)
• Consequence: MAGEL2 NM_019066.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.50

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 (BayesDel_noAF=-0.82).
• BP6: Variant 15-23643744-A-T is Benign according to our data. Variant chr15-23643744-A-T is described in ClinVar as [Benign]. Clinvar id is 1233500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.876 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGEL2	NM_019066.5	c.*249T>A		3_prime_UTR_variant	1/1	ENST00000650528.1	NP_061939.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGEL2	ENST00000650528	c.*249T>A		3_prime_UTR_variant	1/1		NM_019066.5	ENSP00000497810.1

Frequencies

GnomAD3 genomes AF: 0.674 AC: 102506 AN: 151984 Hom.: 36201 Cov.: 33

Gnomad AFR AF: 0.884

Gnomad AMI AF: 0.633

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.766

Gnomad FIN AF: 0.595

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.669

GnomAD4 exome AF: 0.597 AC: 149225 AN: 250016 Hom.: 46009 Cov.: 3 AF XY: 0.595 AC XY: 74958 AN XY: 126020

Gnomad4 AFR exome AF: 0.887

Gnomad4 AMR exome AF: 0.684

Gnomad4 ASJ exome AF: 0.585

Gnomad4 EAS exome AF: 0.793

Gnomad4 SAS exome AF: 0.746

Gnomad4 FIN exome AF: 0.582

Gnomad4 NFE exome AF: 0.548

Gnomad4 OTH exome AF: 0.620

GnomAD4 genome AF: 0.675 AC: 102611 AN: 152102 Hom.: 36244 Cov.: 33 AF XY: 0.680 AC XY: 50566 AN XY: 74352

Gnomad4 AFR AF: 0.884

Gnomad4 AMR AF: 0.673

Gnomad4 ASJ AF: 0.602

Gnomad4 EAS AF: 0.777

Gnomad4 SAS AF: 0.766

Gnomad4 FIN AF: 0.595

Gnomad4 NFE AF: 0.550

Gnomad4 OTH AF: 0.668

Alfa AF: 0.620 Hom.: 3607

Bravo AF: 0.686

Asia WGS AF: 0.782 AC: 2717 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.81
DANN	Benign	0.75

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: rs8920; hg19: chr15-23888891;