rs377449787

chr19-7556454-G-Cchr19-7556454-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1 PM2 PP2 BP4_Strong

The NM_001166114.2(PNPLA6):c.3095G>C(p.Ser1032Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000368 in 1,602,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: PNPLA6 NM_001166114.2 missense, splice_region
• Scores: Splicing: ADA: 0.00001767
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -0.122

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001166114.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PNPLA6
• BP4: Computational evidence support a benign effect (MetaRNN=0.044030935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA6	NM_001166114.2	c.3095G>C	p.Ser1032Thr	missense_variant, splice_region_variant	25/32	ENST00000600737.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA6	ENST00000600737.6	c.3095G>C	p.Ser1032Thr	missense_variant, splice_region_variant	25/32	1	NM_001166114.2	P3

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152072 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251478 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000324 AC: 47 AN: 1449960 Hom.: 0 Cov.: 30 AF XY: 0.0000180 AC XY: 13 AN XY: 722062

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.000617

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152190 Hom.: 0 Cov.: 30 AF XY: 0.0000134 AC XY: 1 AN XY: 74402

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0000225 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 39 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2022	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 994 of the PNPLA6 protein (p.Ser994Thr). This variant is present in population databases (rs377449787, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PNPLA6-related conditions. ClinVar contains an entry for this variant (Variation ID: 240694). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2022

The c.2981G>C (p.S994T) alteration is located in exon 28 (coding exon 26) of the PNPLA6 gene. This alteration results from a G to C substitution at nucleotide position 2981, causing the serine (S) at amino acid position 994 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Laurence-Moon syndrome;C1848745:Trichomegaly-retina pigmentary degeneration-dwarfism syndrome;C1859093:Ataxia-hypogonadism-choroidal dystrophy syndrome;C2677586:Hereditary spastic paraplegia 39 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

May 01, 2023

BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	17
Dann	Benign	0.51
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.81
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.044	T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N;N;N;N;.;.
REVEL	Benign	0.072
Sift	Benign	0.27	T;T;T;T;.;.
Sift4G	Benign	0.42	T;T;T;T;T;.
Polyphen		0.0070	B;.;.;B;.;.
Vest4		0.22
MVP		0.40
MPC		0.85
ClinPred		0.033	T
GERP RS		1.4
Varity_R		0.045
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0
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: rs377449787; hg19: chr19-7621340;