chr19-7561524-C-G

Variant names:

• chr19-7561524-C-G
• rs150392453
• NM_001166114.2:c.4060C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PM1 PM2 PP2 BP4_Strong

The NM_001166111.2(PNPLA6):​c.4090C>G​(p.Leu1364Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,456,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L1364L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: PNPLA6 NM_001166111.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.66
• Publications: 1 publications found

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]

PNPLA6 Gene-Disease associations (from GenCC):

• ataxia-hypogonadism-choroidal dystrophy syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• PNPLA6-related spastic paraplegia with or without ataxia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 39

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• cerebellar ataxia-hypogonadism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Laurence-Moon syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• trichomegaly-retina pigmentary degeneration-dwarfism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 3 benign, 8 uncertain in NM_001166111.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PNPLA6 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 4.3547 (above the threshold of 3.09). Trascript score misZ: 3.4354 (above the threshold of 3.09). GenCC associations: The gene is linked to retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome, cerebellar ataxia-hypogonadism syndrome, PNPLA6-related spastic paraplegia with or without ataxia, ataxia-hypogonadism-choroidal dystrophy syndrome, trichomegaly-retina pigmentary degeneration-dwarfism syndrome, hereditary spastic paraplegia 39, Laurence-Moon syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.037819624).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166111.2. 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
	PNPLA6	NM_001166114.2	MANE Select	c.4060C>G	p.Leu1354Val	missense	Exon 32 of 32	NP_001159586.1
	PNPLA6	NM_001166111.2		c.4090C>G	p.Leu1364Val	missense	Exon 34 of 34	NP_001159583.1
	PNPLA6	NM_001166113.1		c.3946C>G	p.Leu1316Val	missense	Exon 35 of 35	NP_001159585.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA6	ENST00000600737.6	TSL:1 MANE Select	c.4060C>G	p.Leu1354Val	missense	Exon 32 of 32	ENSP00000473211.1
	PNPLA6	ENST00000221249.10	TSL:1	c.3946C>G	p.Leu1316Val	missense	Exon 35 of 35	ENSP00000221249.5
	PNPLA6	ENST00000450331.7	TSL:1	c.3946C>G	p.Leu1316Val	missense	Exon 35 of 35	ENSP00000394348.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000127 AC: 3 AN: 236928 AF XY: 0.0000233

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000944

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1456536 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 724046

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 44216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39522

South Asian (SAS) AF: 0.000129 AC: 11 AN: 85236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52438

Middle Eastern (MID) AF: 0.000191 AC: 1 AN: 5248

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110414

Other (OTH) AF: 0.0000166 AC: 1 AN: 60078

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 39 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.61
DANN	Benign	0.73
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0079	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.93	T
PhyloP100		-1.7
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.0060
Sift	Benign	0.18	T
Sift4G	Benign	0.76	T
Polyphen		0.0010	B
Vest4		0.029
MVP		0.11
MPC		0.93
ClinPred		0.048	T
GERP RS		-8.7
Varity_R		0.021
gMVP		0.11
Mutation Taster		=96/4	polymorphism

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: rs150392453; hg19: chr19-7626410;