rs35732838

Variant names:

• chr19-7535971-G-A
• rs35732838
• NM_001166114.2:c.183G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001166114.2(PNPLA6):​c.183G>A​(p.Val61Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00781 in 1,581,270 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (71 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (101 hom.)
• Consequence: PNPLA6 NM_001166114.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.992
• 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: 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 19-7535971-G-A is Benign according to our data. Variant chr19-7535971-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 330512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.992 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0512 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166114.2. 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_001166114.2	MANE Select	c.183G>A	p.Val61Val	synonymous	Exon 1 of 32	NP_001159586.1	A0A384DVU0
	PNPLA6	NM_001166111.2		c.210G>A	p.Val70Val	synonymous	Exon 3 of 34	NP_001159583.1	Q8IY17-4
	PNPLA6	NM_001166113.1		c.66G>A	p.Val22Val	synonymous	Exon 4 of 35	NP_001159585.1	Q8IY17-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA6	ENST00000600737.6	TSL:1 MANE Select	c.183G>A	p.Val61Val	synonymous	Exon 1 of 32	ENSP00000473211.1	A0A384DVU0
	PNPLA6	ENST00000221249.10	TSL:1	c.66G>A	p.Val22Val	synonymous	Exon 4 of 35	ENSP00000221249.5	Q8IY17-2
	PNPLA6	ENST00000450331.7	TSL:1	c.66G>A	p.Val22Val	synonymous	Exon 4 of 35	ENSP00000394348.2	Q8IY17-2

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2842 AN: 152114 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.0531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.00515

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.00849 AC: 1660 AN: 195420 AF XY: 0.00752

Gnomad AFR exome AF: 0.0554

Gnomad AMR exome AF: 0.00735

Gnomad ASJ exome AF: 0.0245

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000978

Gnomad NFE exome AF: 0.00519

Gnomad OTH exome AF: 0.00881

GnomAD4 exome AF: 0.00666 AC: 9511 AN: 1429038 Hom.: 101 Cov.: 32 AF XY: 0.00640 AC XY: 4532 AN XY: 708616

African (AFR) AF: 0.0574 AC: 1909 AN: 33274

American (AMR) AF: 0.00818 AC: 325 AN: 39714

Ashkenazi Jewish (ASJ) AF: 0.0237 AC: 605 AN: 25526

East Asian (EAS) AF: 0.0000518 AC: 2 AN: 38596

South Asian (SAS) AF: 0.000969 AC: 80 AN: 82534

European-Finnish (FIN) AF: 0.00138 AC: 64 AN: 46302

Middle Eastern (MID) AF: 0.0272 AC: 152 AN: 5596

European-Non Finnish (NFE) AF: 0.00531 AC: 5833 AN: 1098254

Other (OTH) AF: 0.00913 AC: 541 AN: 59242

GnomAD4 genome AF: 0.0187 AC: 2845 AN: 152232 Hom.: 71 Cov.: 32 AF XY: 0.0178 AC XY: 1326 AN XY: 74434

African (AFR) AF: 0.0531 AC: 2203 AN: 41526

American (AMR) AF: 0.0105 AC: 161 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4832

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.00515 AC: 350 AN: 68010

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

Alfa AF: 0.0141 Hom.: 17

Bravo AF: 0.0219

Asia WGS AF: 0.00549 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Hereditary spastic paraplegia 39 (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Mucolipidosis type IV (1)
-	-	1	not provided (1)
-	-	1	Spastic Paraplegia, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.82
PhyloP100		0.99
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35732838; hg19: chr19-7600857;