rs540516

Variant names:

• chr19-7534329-C-T
• rs540516
• ENST00000221249.10:c.-196+90C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001166112.2(PNPLA6):​c.-313C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 216,762 control chromosomes in the GnomAD database, including 6,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5009 hom., cov: 31)
  • Exomes 𝑓: 0.22 (1889 hom.)
• Consequence: PNPLA6 NM_001166112.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.306
• Publications: 3 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

ENSG00000268614 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-7534329-C-T is Benign according to our data. Variant chr19-7534329-C-T is described in ClinVar as Benign. ClinVar VariationId is 1526319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166112.2. 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_001166112.2		c.-313C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 34	NP_001159584.1	Q8IY17-5
	PNPLA6	NM_001166112.2		c.-313C>T		5_prime_UTR	Exon 1 of 34	NP_001159584.1	Q8IY17-5
	PNPLA6	NM_006702.5		c.-196+90C>T		intron	N/A	NP_006693.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA6	ENST00000221249.10	TSL:1	c.-196+90C>T		intron	N/A	ENSP00000221249.5	Q8IY17-2
	ENSG00000268614	ENST00000601870.1	TSL:4	n.*151-50C>T		intron	N/A	ENSP00000471492.1	M0R0W3
	PNPLA6	ENST00000545201.6	TSL:2	c.-313C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 34	ENSP00000443323.1	Q8IY17-5

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38344 AN: 151824 Hom.: 4988 Cov.: 31

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.220

GnomAD4 exome AF: 0.221 AC: 14296 AN: 64818 Hom.: 1889 Cov.: 0 AF XY: 0.215 AC XY: 7379 AN XY: 34368

African (AFR) AF: 0.168 AC: 293 AN: 1746

American (AMR) AF: 0.293 AC: 1076 AN: 3670

Ashkenazi Jewish (ASJ) AF: 0.0953 AC: 125 AN: 1312

East Asian (EAS) AF: 0.282 AC: 887 AN: 3148

South Asian (SAS) AF: 0.190 AC: 2141 AN: 11260

European-Finnish (FIN) AF: 0.236 AC: 603 AN: 2552

Middle Eastern (MID) AF: 0.0714 AC: 15 AN: 210

European-Non Finnish (NFE) AF: 0.224 AC: 8466 AN: 37772

Other (OTH) AF: 0.219 AC: 690 AN: 3148

GnomAD4 genome AF: 0.253 AC: 38396 AN: 151944 Hom.: 5009 Cov.: 31 AF XY: 0.251 AC XY: 18656 AN XY: 74258

African (AFR) AF: 0.214 AC: 8853 AN: 41440

American (AMR) AF: 0.283 AC: 4321 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 505 AN: 3470

East Asian (EAS) AF: 0.295 AC: 1520 AN: 5160

South Asian (SAS) AF: 0.230 AC: 1108 AN: 4812

European-Finnish (FIN) AF: 0.307 AC: 3242 AN: 10562

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18137 AN: 67930

Other (OTH) AF: 0.221 AC: 464 AN: 2102

Alfa AF: 0.263 Hom.: 1864

Bravo AF: 0.250

Asia WGS AF: 0.288 AC: 998 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.7
DANN	Benign	0.82
PhyloP100		-0.31
PromoterAI		-0.017	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs540516; hg19: chr19-7599215;