rs535099488

Variant names:

• chr19-35745610-A-G
• rs535099488
• ENST00000591949.1:c.-187A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000591949.1(PSENEN):​c.-187A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000822 in 632,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: PSENEN ENST00000591949.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.66
• 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]

U2AF1L4 (HGNC:23020): (U2 small nuclear RNA auxiliary factor 1 like 4) Predicted to enable pre-mRNA 3'-splice site binding activity. Predicted to be involved in mRNA splicing, via spliceosome. Predicted to be located in nucleoplasm. Predicted to be part of U2AF complex and spliceosomal complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000267120 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 19-35745610-A-G is Benign according to our data. Variant chr19-35745610-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3048196.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
U2AF1L4	NM_001040425.3	c.-219T>C		upstream_gene_variant		ENST00000378975.8	NP_001035515.1
PSENEN	NM_172341.4	c.-187A>G		upstream_gene_variant		ENST00000587708.7	NP_758844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
U2AF1L4	ENST00000378975.8	c.-219T>C		upstream_gene_variant		1	NM_001040425.3	ENSP00000368258.2
PSENEN	ENST00000587708.7	c.-187A>G		upstream_gene_variant		1	NM_172341.4	ENSP00000468411.1
ENSG00000267120	ENST00000589807.1	n.-219T>C		upstream_gene_variant		2		ENSP00000472696.1
ENSG00000188223	ENST00000591613.2	n.-187A>G		upstream_gene_variant		2		ENSP00000468389.2

Frequencies

GnomAD3 genomes AF: 0.000190 AC: 29 AN: 152244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.0000479 AC: 23 AN: 480442 Hom.: 0 Cov.: 5 AF XY: 0.0000274 AC XY: 7 AN XY: 255072

African (AFR) AF: 0.00 AC: 0 AN: 12914

American (AMR) AF: 0.000733 AC: 14 AN: 19110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13988

East Asian (EAS) AF: 0.00 AC: 0 AN: 31666

South Asian (SAS) AF: 0.00 AC: 0 AN: 47508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2036

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 295192

Other (OTH) AF: 0.000331 AC: 9 AN: 27220

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152362 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74502

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.00176 AC: 27 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000453

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PSENEN-related disorder Benign:1

Oct 12, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Benign	0.73
PhyloP100		1.7
PromoterAI		-0.10	Neutral

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: rs535099488; hg19: chr19-36236511;