rs188353745

Positions:

• chr19-7535961-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001166114.2(PNPLA6):​c.173T>C​(p.Val58Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00398 in 1,583,718 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (121 hom.)
• Consequence: PNPLA6 NM_001166114.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.70

Genes affected

PNPLA6 (HGNC:16268): (patatin like phospholipase domain containing 6) This gene encodes a phospholipase that deacetylates intracellular phosphatidylcholine to produce glycerophosphocholine. It is thought to function in neurite outgrowth and process elongation during neuronal differentiation. The protein is anchored to the cytoplasmic face of the endoplasmic reticulum in both neurons and non-neuronal cells. Mutations in this gene result in autosomal recessive spastic paraplegia, and the protein is the target for neurodegeneration induced by organophosphorus compounds and chemical warfare agents. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ENSG00000268614 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PNPLA6. . Gene score misZ 4.3547 (greater than the threshold 3.09). Trascript score misZ 3.5139 (greater than threshold 3.09). GenCC has associacion of gene with trichomegaly-retina pigmentary degeneration-dwarfism syndrome, ataxia-hypogonadism-choroidal dystrophy syndrome, Laurence-Moon syndrome, cerebellar ataxia-hypogonadism syndrome, retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome, PNPLA6-related spastic paraplegia with or without ataxia, hereditary spastic paraplegia 39.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0031965077).
• BP6: Variant 19-7535961-T-C is Benign according to our data. Variant chr19-7535961-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 281419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00407 (619/151918) while in subpopulation EAS AF= 0.0476 (245/5142). AF 95% confidence interval is 0.0428. There are 11 homozygotes in gnomad4. There are 401 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA6	NM_001166114.2	c.173T>C	p.Val58Ala	missense_variant	1/32	ENST00000600737.6	NP_001159586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA6	ENST00000600737.6	c.173T>C	p.Val58Ala	missense_variant	1/32	1	NM_001166114.2	ENSP00000473211.1
ENSG00000268614	ENST00000601870.1	n.*469T>C		non_coding_transcript_exon_variant	7/10	4		ENSP00000471492.1
ENSG00000268614	ENST00000601870.1	n.*469T>C		3_prime_UTR_variant	7/10	4		ENSP00000471492.1

Frequencies

GnomAD3 genomes AF: 0.00408 AC: 619 AN: 151800 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0475

Gnomad SAS AF: 0.0411

Gnomad FIN AF: 0.00643

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.0104 AC: 2099 AN: 202596 Hom.: 44 AF XY: 0.0121 AC XY: 1327 AN XY: 109468

Gnomad AFR exome AF: 0.000764

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0466

Gnomad SAS exome AF: 0.0409

Gnomad FIN exome AF: 0.00667

Gnomad NFE exome AF: 0.000566

Gnomad OTH exome AF: 0.00430

GnomAD4 exome AF: 0.00397 AC: 5689 AN: 1431800 Hom.: 121 Cov.: 32 AF XY: 0.00501 AC XY: 3559 AN XY: 710232

Gnomad4 AFR exome AF: 0.000540

Gnomad4 AMR exome AF: 0.00326

Gnomad4 ASJ exome AF: 0.0000391

Gnomad4 EAS exome AF: 0.0419

Gnomad4 SAS exome AF: 0.0374

Gnomad4 FIN exome AF: 0.00507

Gnomad4 NFE exome AF: 0.000209

Gnomad4 OTH exome AF: 0.00567

GnomAD4 genome AF: 0.00407 AC: 619 AN: 151918 Hom.: 11 Cov.: 32 AF XY: 0.00540 AC XY: 401 AN XY: 74230

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0476

Gnomad4 SAS AF: 0.0412

Gnomad4 FIN AF: 0.00643

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.000833 Hom.: 0

Bravo AF: 0.00335

ExAC AF: 0.00916 AC: 1095

Asia WGS AF: 0.0370 AC: 128 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 04, 2016	- -

Hereditary spastic paraplegia 39 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

Mucolipidosis type IV Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 16, 2021

- -

Spastic Paraplegia, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.57
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	.;T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.060
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.76	.;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0032	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.1	N;.;.;N;.;N;N;.;.;.
REVEL	Benign	0.064
Sift	Benign	0.041	D;.;.;D;.;T;D;.;.;.
Sift4G	Benign	0.20	T;T;T;T;D;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.;B;.;.;.
Vest4		0.21
MPC		2.4
ClinPred		0.013	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.096
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs188353745; hg19: chr19-7600847;