rs1970571358

Variant names:

• chr19-35746430-T-C
• rs1970571358
• NM_172341.4:c.73T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_172341.4(PSENEN):​c.73T>C​(p.Phe25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PSENEN NM_172341.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13
• Publications: 0 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 3 ACMG points.

• PM1: In a mutagenesis_site Decreased APP processing by the gamma-secretase complex. (size 0) in uniprot entity PEN2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27456778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSENEN	NM_172341.4	c.73T>C	p.Phe25Leu	missense_variant	Exon 3 of 4	ENST00000587708.7	NP_758844.1
PSENEN	NM_001281532.3	c.73T>C	p.Phe25Leu	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.73T>C	p.Phe25Leu	missense_variant	Exon 3 of 4	1	NM_172341.4	ENSP00000468411.1
PSENEN	ENST00000222266.2	c.73T>C	p.Phe25Leu	missense_variant	Exon 3 of 4	1		ENSP00000222266.1
ENSG00000188223	ENST00000591613.2	n.73T>C		non_coding_transcript_exon_variant	Exon 3 of 11	2		ENSP00000468389.2
PSENEN	ENST00000591949.1	c.73T>C	p.Phe25Leu	missense_variant	Exon 3 of 3	2		ENSP00000468593.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461472 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727080

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111896

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.73T>C (p.F25L) alteration is located in exon 3 (coding exon 2) of the PSENEN gene. This alteration results from a T to C substitution at nucleotide position 73, causing the phenylalanine (F) at amino acid position 25 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.40	T;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.097
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.39	N;.;N
PhyloP100		3.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.5	.;.;N
REVEL	Benign	0.14
Sift	Benign	0.68	.;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.31
MutPred		0.73		Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);
MVP		0.49
MPC		0.73
ClinPred		0.67	D
GERP RS		4.3
Varity_R		0.46
gMVP		0.77
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1970571358; hg19: chr19-36237331;