rs1555738906

Variant names:

• chr19-35746735-T-G
• rs1555738906
• NM_172341.4:c.194T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 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). Synonymous variant affecting the same amino acid position (i.e. L65L) has been classified as Likely benign.

• 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
• Publications: 1 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: Likely_pathogenic. The variant received 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 VariationId is 446484.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSENEN	NM_172341.4	c.194T>G	p.Leu65Arg	missense_variant	Exon 4 of 4	ENST00000587708.7	NP_758844.1
PSENEN	NM_001281532.3	c.194T>G	p.Leu65Arg	missense_variant	Exon 4 of 4		NP_001268461.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSENEN	ENST00000587708.7	c.194T>G	p.Leu65Arg	missense_variant	Exon 4 of 4	1	NM_172341.4	ENSP00000468411.1
PSENEN	ENST00000222266.2	c.194T>G	p.Leu65Arg	missense_variant	Exon 4 of 4	1		ENSP00000222266.1
ENSG00000188223	ENST00000591613.2	n.166+212T>G		intron_variant	Intron 3 of 10	2		ENSP00000468389.2
PSENEN	ENST00000591949.1	c.*84T>G		3_prime_UTR_variant	Exon 3 of 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

Dec 01, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
PhyloP100		4.1
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
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555738906; hg19: chr19-36237636;