rs112133109

Variant names:

• chr19-7559055-G-A
• rs112133109
• NM_001166114.2:c.3603G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-7559055-G-A
• chr19-7559055-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001166114.2(PNPLA6):​c.3603G>A​(p.Gln1201Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,614,218 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (13 hom., cov: 33)
  • Exomes 𝑓: 0.013 (140 hom.)
• Consequence: PNPLA6 NM_001166114.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.68
• Publications: 7 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 19-7559055-G-A is Benign according to our data. Variant chr19-7559055-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.68 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00918 (1399/152356) while in subpopulation NFE AF = 0.0137 (933/68028). AF 95% confidence interval is 0.013. There are 13 homozygotes in GnomAd4. There are 677 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

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.3603G>A	p.Gln1201Gln	synonymous	Exon 28 of 32	NP_001159586.1	A0A384DVU0
	PNPLA6	NM_001166111.2		c.3633G>A	p.Gln1211Gln	synonymous	Exon 30 of 34	NP_001159583.1	Q8IY17-4
	PNPLA6	NM_001166113.1		c.3489G>A	p.Gln1163Gln	synonymous	Exon 31 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.3603G>A	p.Gln1201Gln	synonymous	Exon 28 of 32	ENSP00000473211.1	A0A384DVU0
	PNPLA6	ENST00000221249.10	TSL:1	c.3489G>A	p.Gln1163Gln	synonymous	Exon 31 of 35	ENSP00000221249.5	Q8IY17-2
	PNPLA6	ENST00000450331.7	TSL:1	c.3489G>A	p.Gln1163Gln	synonymous	Exon 31 of 35	ENSP00000394348.2	Q8IY17-2

Frequencies

GnomAD3 genomes AF: 0.00921 AC: 1402 AN: 152238 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00248

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00896

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.0106 AC: 2661 AN: 251440 AF XY: 0.0115

Gnomad AFR exome AF: 0.00339

Gnomad AMR exome AF: 0.00627

Gnomad ASJ exome AF: 0.00536

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.0128 AC: 18717 AN: 1461862 Hom.: 140 Cov.: 36 AF XY: 0.0129 AC XY: 9350 AN XY: 727232

African (AFR) AF: 0.00257 AC: 86 AN: 33480

American (AMR) AF: 0.00642 AC: 287 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00429 AC: 112 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00780 AC: 673 AN: 86258

European-Finnish (FIN) AF: 0.0138 AC: 736 AN: 53412

Middle Eastern (MID) AF: 0.0260 AC: 150 AN: 5768

European-Non Finnish (NFE) AF: 0.0144 AC: 15962 AN: 1111990

Other (OTH) AF: 0.0117 AC: 709 AN: 60394

GnomAD4 genome AF: 0.00918 AC: 1399 AN: 152356 Hom.: 13 Cov.: 33 AF XY: 0.00909 AC XY: 677 AN XY: 74508

African (AFR) AF: 0.00248 AC: 103 AN: 41582

American (AMR) AF: 0.00889 AC: 136 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00517 AC: 25 AN: 4832

European-Finnish (FIN) AF: 0.0124 AC: 132 AN: 10624

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0137 AC: 933 AN: 68028

Other (OTH) AF: 0.0156 AC: 33 AN: 2116

Alfa AF: 0.0115 Hom.: 38

Bravo AF: 0.00874

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0171

EpiControl AF: 0.0187

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary spastic paraplegia 39 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	5.7
DANN	Benign	0.78
PhyloP100		2.7
PromoterAI		-0.014	Neutral
Mutation Taster		=100/0	polymorphism

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: rs112133109; hg19: chr19-7623941; COSMIC: COSV55386447; COSMIC: COSV55386447;