rs3817622

Variant names:

• chr19-35746326-T-A
• rs3817622
• NM_172341.4:c.62-93T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_172341.4(PSENEN):​c.62-93T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0974 in 1,125,906 control chromosomes in the GnomAD database, including 5,964 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.099 (843 hom., cov: 32)
  • Exomes 𝑓: 0.097 (5121 hom.)
• Consequence: PSENEN NM_172341.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.598
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0995 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172341.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSENEN	NM_172341.4	MANE Select	c.62-93T>A		intron	N/A	NP_758844.1
	PSENEN	NM_001281532.3		c.62-93T>A		intron	N/A	NP_001268461.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSENEN	ENST00000587708.7	TSL:1 MANE Select	c.62-93T>A		intron	N/A	ENSP00000468411.1
	PSENEN	ENST00000222266.2	TSL:1	c.62-93T>A		intron	N/A	ENSP00000222266.1
	ENSG00000188223	ENST00000591613.2	TSL:2	n.62-93T>A		intron	N/A	ENSP00000468389.2

Frequencies

GnomAD3 genomes AF: 0.0993 AC: 15084 AN: 151928 Hom.: 842 Cov.: 32

Gnomad AFR AF: 0.0831

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.0895

Gnomad ASJ AF: 0.0685

Gnomad EAS AF: 0.0879

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0998

Gnomad OTH AF: 0.0798

GnomAD4 exome AF: 0.0971 AC: 94572 AN: 973860 Hom.: 5121 AF XY: 0.0983 AC XY: 49469 AN XY: 503468

African (AFR) AF: 0.0866 AC: 2072 AN: 23934

American (AMR) AF: 0.106 AC: 4331 AN: 40734

Ashkenazi Jewish (ASJ) AF: 0.0620 AC: 1412 AN: 22768

East Asian (EAS) AF: 0.0810 AC: 3026 AN: 37354

South Asian (SAS) AF: 0.111 AC: 8280 AN: 74706

European-Finnish (FIN) AF: 0.185 AC: 7403 AN: 40092

Middle Eastern (MID) AF: 0.0559 AC: 274 AN: 4898

European-Non Finnish (NFE) AF: 0.0933 AC: 63874 AN: 684824

Other (OTH) AF: 0.0875 AC: 3900 AN: 44550

GnomAD4 genome AF: 0.0994 AC: 15106 AN: 152046 Hom.: 843 Cov.: 32 AF XY: 0.104 AC XY: 7728 AN XY: 74336

African (AFR) AF: 0.0831 AC: 3449 AN: 41484

American (AMR) AF: 0.0901 AC: 1377 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0685 AC: 237 AN: 3462

East Asian (EAS) AF: 0.0883 AC: 456 AN: 5164

South Asian (SAS) AF: 0.107 AC: 515 AN: 4808

European-Finnish (FIN) AF: 0.184 AC: 1940 AN: 10568

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0998 AC: 6783 AN: 67956

Other (OTH) AF: 0.0799 AC: 169 AN: 2114

Alfa AF: 0.110 Hom.: 128

Bravo AF: 0.0896

Asia WGS AF: 0.100 AC: 346 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	16
DANN	Benign	0.83
PhyloP100		0.60
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3817622; hg19: chr19-36237227; COSMIC: COSV53073523; COSMIC: COSV53073523;