15-24967964-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394334.1(SNURF):c.143A>T(p.Gln48Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q48R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNURF NM_001394334.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51

Genes affected

SNURF (HGNC:11171): (SNRPN upstream open reading frame) This gene is located within the Prader-Willi Syndrome critical region on chromosome 15. Transcripts produced from this gene initiate at an imprinting center and are paternally-imprinted. These transcripts may be bicistronic and also encode SNRPN (small nuclear ribonucleoprotein polypeptide N) from a downstream open reading frame. The small protein represented by this gene is encoded by an evolutionarily-conserved upstream open reading frame and is localized to the nucleus. Extensive alternative splicing and promoter usage occurs in this region and the full-length nature of some of these transcripts has not been determined. Alterations in the imprinting center are associated with parental imprint switch failure, which may cause Angelman syndrome or Prader-Willi syndrome. [provided by RefSeq, Mar 2017]

SNRPN (HGNC:11164): (small nuclear ribonucleoprotein polypeptide N) This gene is located within the Prader-Willi Syndrome critical region on chromosome 15 and is imprinted and expressed from the paternal allele. It encodes a component of the small nuclear ribonucleoprotein complex, which functions in pre-mRNA processing and may contribute to tissue-specific alternative splicing. Alternative promoter use and alternative splicing result in a multitude of transcript variants encoding the same protein. Transcript variants that initiate at the CpG island-associated imprinting center may be bicistronic and also encode the SNRPN upstream reading frame protein (SNURF) from an upstream open reading frame. In addition, long spliced transcripts for small nucleolar RNA host gene 14 (SNHG14) may originate from the promoters at this locus and share exons with this gene. Alterations in this region are associated with parental imprint switch failure, which may cause Angelman syndrome or Prader-Willi syndrome. [provided by RefSeq, Mar 2017]

SNHG14 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1928581).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNURF	NM_001394334.1	c.143A>T	p.Gln48Leu	missense_variant	3/3	ENST00000577949.6
SNRPN	NM_003097.6	c.-262A>T		5_prime_UTR_variant	3/10	ENST00000390687.9
SNHG14	NR_146177.1	n.641A>T		non_coding_transcript_exon_variant	6/148

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNURF	ENST00000577949.6	c.143A>T	p.Gln48Leu	missense_variant	3/3	2	NM_001394334.1	P1
SNRPN	ENST00000390687.9	c.-262A>T		5_prime_UTR_variant	3/10	1	NM_003097.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autism spectrum disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.51	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;N;N;N
PrimateAI	Uncertain	0.71	T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.029	B;B
Vest4		0.40
MutPred		0.56		Loss of solvent accessibility (P = 0.0087);Loss of solvent accessibility (P = 0.0087);
MVP		0.13
ClinPred		0.36	T
GERP RS		3.5
Varity_R		0.087
gMVP		0.067

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: rs765651266; hg19: chr15-25213111;