1-40087661-G-T

Variant names:

• chr1-40087661-G-T
• rs7513553
• NM_000310.4:c.536+1749C>A

Variant summary

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

The NM_000310.4(PPT1):​c.536+1749C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 151,866 control chromosomes in the GnomAD database, including 5,475 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 0.26 (5475 hom., cov: 32)
• Consequence: PPT1 NM_000310.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0660
• Publications: 3 publications found

Genes affected

PPT1 (HGNC:9325): (palmitoyl-protein thioesterase 1) The protein encoded by this gene is a small glycoprotein involved in the catabolism of lipid-modified proteins during lysosomal degradation. The encoded enzyme removes thioester-linked fatty acyl groups such as palmitate from cysteine residues. Defects in this gene are a cause of infantile neuronal ceroid lipofuscinosis 1 (CLN1, or INCL) and neuronal ceroid lipofuscinosis 4 (CLN4). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Dec 2008]

PPT1 Gene-Disease associations (from GenCC):

• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000310.4. 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
	PPT1	NM_000310.4	MANE Select	c.536+1749C>A		intron	N/A	NP_000301.1
	PPT1	NM_001363695.2		c.536+1749C>A		intron	N/A	NP_001350624.1
	PPT1	NM_001142604.2		c.227+1749C>A		intron	N/A	NP_001136076.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPT1	ENST00000642050.2	MANE Select	c.536+1749C>A		intron	N/A	ENSP00000493153.1
	PPT1	ENST00000433473.8	TSL:1	c.533+1749C>A		intron	N/A	ENSP00000394863.4
	PPT1	ENST00000530704.6	TSL:1	n.*159+1749C>A		intron	N/A	ENSP00000431655.1

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38816 AN: 151748 Hom.: 5459 Cov.: 32

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.216

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.256 AC: 38879 AN: 151866 Hom.: 5475 Cov.: 32 AF XY: 0.263 AC XY: 19539 AN XY: 74198

African (AFR) AF: 0.339 AC: 14034 AN: 41446

American (AMR) AF: 0.241 AC: 3672 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 543 AN: 3470

East Asian (EAS) AF: 0.394 AC: 2008 AN: 5096

South Asian (SAS) AF: 0.341 AC: 1638 AN: 4808

European-Finnish (FIN) AF: 0.288 AC: 3040 AN: 10546

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.196 AC: 13321 AN: 67980

Other (OTH) AF: 0.219 AC: 462 AN: 2108

Alfa AF: 0.205 Hom.: 6035

Bravo AF: 0.257

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	5.1
DANN	Benign	0.54
PhyloP100		0.066
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: rs7513553; hg19: chr1-40553333;