rs72937434

Variant names:

• chr1-40074145-C-G
• rs72937434
• NM_000310.4:c.837G>C
• PPT1 p.Gln279His

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000310.4(PPT1):​c.837G>C​(p.Gln279His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,614,148 control chromosomes in the GnomAD database, including 254 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (128 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (126 hom.)
• Consequence: PPT1 NM_000310.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.09
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P, ClinGen, Myriad Women's Health

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062122345).
• BP6: Variant 1-40074145-C-G is Benign according to our data. Variant chr1-40074145-C-G is described in ClinVar as Benign. ClinVar VariationId is 130023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.078 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPT1	NM_000310.4	MANE Select	c.837G>C	p.Gln279His	missense	Exon 9 of 9	NP_000301.1	P50897-1
	PPT1	NM_001363695.2		c.765G>C	p.Gln255His	missense	Exon 8 of 8	NP_001350624.1	Q5T0S4
	PPT1	NM_001142604.2		c.528G>C	p.Gln176His	missense	Exon 6 of 6	NP_001136076.1	P50897-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPT1	ENST00000642050.2	MANE Select	c.837G>C	p.Gln279His	missense	Exon 9 of 9	ENSP00000493153.1	P50897-1
	PPT1	ENST00000433473.8	TSL:1	c.834G>C	p.Gln278His	missense	Exon 9 of 9	ENSP00000394863.4	A0A2C9F2P4
	PPT1	ENST00000530704.6	TSL:1	n.*460G>C		non_coding_transcript_exon	Exon 9 of 9	ENSP00000431655.1	E9PK48

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3480 AN: 152182 Hom.: 127 Cov.: 32

Gnomad AFR AF: 0.0803

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.00560 AC: 1409 AN: 251434 AF XY: 0.00426

Gnomad AFR exome AF: 0.0789

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00237 AC: 3460 AN: 1461848 Hom.: 126 Cov.: 31 AF XY: 0.00201 AC XY: 1459 AN XY: 727224

African (AFR) AF: 0.0858 AC: 2873 AN: 33476

American (AMR) AF: 0.00293 AC: 131 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000117 AC: 130 AN: 1111978

Other (OTH) AF: 0.00522 AC: 315 AN: 60394

GnomAD4 genome AF: 0.0229 AC: 3487 AN: 152300 Hom.: 128 Cov.: 32 AF XY: 0.0221 AC XY: 1648 AN XY: 74480

African (AFR) AF: 0.0803 AC: 3336 AN: 41544

American (AMR) AF: 0.00705 AC: 108 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68028

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.00358 Hom.: 14

Bravo AF: 0.0263

Asia WGS AF: 0.00404 AC: 15 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	3	Neuronal ceroid lipofuscinosis 1 (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.027
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.54
Mutation Taster		=80/20	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs72937434;

hg19: chr1-40539817;