19-35746473-G-T

Variant names:

• chr19-35746473-G-T
• rs758352978
• NM_172341.4:c.116G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_172341.4(PSENEN):​c.116G>T​(p.Arg39Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PSENEN NM_172341.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87
• Publications: 5 publications found

Genes affected

PSENEN (HGNC:30100): (presenilin enhancer, gamma-secretase subunit) Presenilins, which are components of the gamma-secretase protein complex, are required for intramembranous processing of some type I transmembrane proteins, such as the Notch proteins and the beta-amyloid precursor protein. Signaling by Notch receptors mediates a wide range of developmental cell fates. Processing of the beta-amyloid precursor protein generates neurotoxic amyloid beta peptides, the major component of senile plaques associated with Alzheimer's disease. This gene encodes a protein that is required for Notch pathway signaling, and for the activity and accumulation of gamma-secretase. Mutations resulting in haploinsufficiency for this gene cause familial acne inversa-2 (ACNINV2). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

PSENEN Gene-Disease associations (from GenCC):

• acne inversa, familial, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Dowling-Degos disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000188223 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSENEN	NM_172341.4	c.116G>T	p.Arg39Leu	missense_variant	Exon 3 of 4	ENST00000587708.7	NP_758844.1
PSENEN	NM_001281532.3	c.116G>T	p.Arg39Leu	missense_variant	Exon 3 of 4		NP_001268461.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSENEN	ENST00000587708.7	c.116G>T	p.Arg39Leu	missense_variant	Exon 3 of 4	1	NM_172341.4	ENSP00000468411.1
PSENEN	ENST00000222266.2	c.116G>T	p.Arg39Leu	missense_variant	Exon 3 of 4	1		ENSP00000222266.1
ENSG00000188223	ENST00000591613.2	n.116G>T		non_coding_transcript_exon_variant	Exon 3 of 11	2		ENSP00000468389.2
PSENEN	ENST00000591949.1	c.116G>T	p.Arg39Leu	missense_variant	Exon 3 of 3	2		ENSP00000468593.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 39 of the PSENEN protein (p.Arg39Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PSENEN-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.;D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.3	M;.;M
PhyloP100		3.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.7	.;.;D
REVEL	Uncertain	0.46
Sift	Benign	0.032	.;.;D
Sift4G	Benign	0.074	T;D;T
Polyphen		0.80	P;.;P
Vest4		0.64
MutPred		0.43		Gain of catalytic residue at W36 (P = 0.256);Gain of catalytic residue at W36 (P = 0.256);Gain of catalytic residue at W36 (P = 0.256);
MVP		0.76
MPC		1.3
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.47
gMVP		0.84
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.29		Position offset: 50

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs758352978; hg19: chr19-36237374;