19-35746735-T-G

Position:

• chr19-35746735-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_172341.4(PSENEN):​c.194T>G​(p.Leu65Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PSENEN NM_172341.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.08

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]

ENSG00000188223 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 19-35746735-T-G is Pathogenic according to our data. Variant chr19-35746735-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 446484.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSENEN	NM_172341.4	c.194T>G	p.Leu65Arg	missense_variant	4/4	ENST00000587708.7	NP_758844.1
PSENEN	NM_001281532.3	c.194T>G	p.Leu65Arg	missense_variant	4/4		NP_001268461.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSENEN	ENST00000587708.7	c.194T>G	p.Leu65Arg	missense_variant	4/4	1	NM_172341.4	ENSP00000468411.1
PSENEN	ENST00000222266.2	c.194T>G	p.Leu65Arg	missense_variant	4/4	1		ENSP00000222266.1
ENSG00000188223	ENST00000591613.2	n.166+212T>G		intron_variant		2		ENSP00000468389.2
PSENEN	ENST00000591949.1	c.*84T>G		3_prime_UTR_variant	3/3	2		ENSP00000468593.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Acne inversa, familial, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	.;T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.4	.;D
REVEL	Pathogenic	0.74
Sift	Benign	0.10	.;T
Sift4G	Benign	0.21	T;T
Polyphen		0.77	P;P
Vest4		0.80
MutPred		0.84		Gain of MoRF binding (P = 0.0131);Gain of MoRF binding (P = 0.0131);
MVP		0.83
MPC		1.8
ClinPred		0.97	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.66
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1555738906; hg19: chr19-36237636;