rs759671675

Variant names:

• chr19-7535560-C-A
• rs759671675
• ENST00000221249.10:c.10C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-7535560-C-A
• chr19-7535560-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001166111.2(PNPLA6):​c.10C>A​(p.Pro4Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PNPLA6 NM_001166111.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.11
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000268614 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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=0.2044603).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA6	NM_001166111.2		c.10C>A	p.Pro4Thr	missense	Exon 2 of 34	NP_001159583.1	Q8IY17-4
	PNPLA6	NM_001166113.1		c.10C>A	p.Pro4Thr	missense	Exon 3 of 35	NP_001159585.1	Q8IY17-2
	PNPLA6	NM_006702.5		c.10C>A	p.Pro4Thr	missense	Exon 3 of 35	NP_006693.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA6	ENST00000221249.10	TSL:1	c.10C>A	p.Pro4Thr	missense	Exon 3 of 35	ENSP00000221249.5	Q8IY17-2
	PNPLA6	ENST00000450331.7	TSL:1	c.10C>A	p.Pro4Thr	missense	Exon 3 of 35	ENSP00000394348.2	Q8IY17-2
	ENSG00000268614	ENST00000601870.1	TSL:4	n.*423C>A		non_coding_transcript_exon	Exon 6 of 10	ENSP00000471492.1	M0R0W3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452200 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721332

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33352

American (AMR) AF: 0.00 AC: 0 AN: 43326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25898

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39370

South Asian (SAS) AF: 0.00 AC: 0 AN: 84370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107902

Other (OTH) AF: 0.00 AC: 0 AN: 59974

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0014	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.86	T
PhyloP100		2.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.098
Sift	Benign	0.19	T
Sift4G	Benign	0.26	T
Polyphen		0.98	D
Vest4		0.40
MutPred		0.26		Gain of sheet (P = 0.0028)
MVP		0.40
MPC		2.2
ClinPred		0.99	D
GERP RS		4.2
PromoterAI		0.057	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.33
Mutation Taster		=82/18	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: rs759671675; hg19: chr19-7600446;