ENST00000221249.10:c.-53T>C

Variant names:

• chr19-7534892-T-C
• rs571796329
• ENST00000221249.10:c.-53T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000221249.10(PNPLA6):​c.-53T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 158,414 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (0 hom.)
• Consequence: PNPLA6 ENST00000221249.10 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.03
• 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: 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00287 (436/152166) while in subpopulation NFE AF = 0.00115 (78/68008). AF 95% confidence interval is 0.000942. There are 7 homozygotes in GnomAd4. There are 315 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000221249.10. 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.-53T>C		5_prime_UTR	Exon 1 of 34	NP_001159583.1	Q8IY17-4
	PNPLA6	NM_001166113.1		c.-129T>C		5_prime_UTR	Exon 1 of 35	NP_001159585.1	Q8IY17-2
	PNPLA6	NM_006702.5		c.-53T>C		5_prime_UTR	Exon 2 of 35	NP_006693.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA6	ENST00000221249.10	TSL:1	c.-53T>C		5_prime_UTR	Exon 2 of 35	ENSP00000221249.5	Q8IY17-2
	PNPLA6	ENST00000450331.7	TSL:1	c.-129T>C		5_prime_UTR	Exon 1 of 35	ENSP00000394348.2	Q8IY17-2
	ENSG00000268614	ENST00000601870.1	TSL:4	n.*361T>C		non_coding_transcript_exon	Exon 5 of 10	ENSP00000471492.1	M0R0W3

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 436 AN: 152048 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0322

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.000958

GnomAD4 exome AF: 0.000640 AC: 4 AN: 6248 Hom.: 0 Cov.: 0 AF XY: 0.000596 AC XY: 2 AN XY: 3356

African (AFR) AF: 0.00 AC: 0 AN: 50

American (AMR) AF: 0.00 AC: 0 AN: 1612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 30

East Asian (EAS) AF: 0.00 AC: 0 AN: 204

South Asian (SAS) AF: 0.00 AC: 0 AN: 1160

European-Finnish (FIN) AF: 0.0250 AC: 1 AN: 40

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.000681 AC: 2 AN: 2938

Other (OTH) AF: 0.00476 AC: 1 AN: 210

GnomAD4 genome AF: 0.00287 AC: 436 AN: 152166 Hom.: 7 Cov.: 32 AF XY: 0.00423 AC XY: 315 AN XY: 74404

African (AFR) AF: 0.00 AC: 0 AN: 41512

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0322 AC: 341 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00115 AC: 78 AN: 68008

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00312 Hom.: 1

Bravo AF: 0.000431

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 39 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	9.1
DANN	Benign	0.75
PhyloP100		-1.0
PromoterAI		0.014	Neutral
Mutation Taster		=299/1	polymorphism

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: rs571796329; hg19: chr19-7599778;