rs746130

Variant names:

• chr19-7535122-T-C
• rs746130
• ENST00000221249.10:c.-43+220T>C

Variant summary

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

The NM_001166113.1(PNPLA6):​c.-118-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 339,980 control chromosomes in the GnomAD database, including 531 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (300 hom., cov: 32)
  • Exomes 𝑓: 0.027 (231 hom.)
• Consequence: PNPLA6 NM_001166113.1 splice_region, intron
• Scores: Splicing: ADA: 0.00007304
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.702
• Publications: 2 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=-0.9).
• BP6: Variant 19-7535122-T-C is Benign according to our data. Variant chr19-7535122-T-C is described in ClinVar as Benign. ClinVar VariationId is 1234448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166113.1. 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.-43+220T>C		intron	N/A	NP_001159583.1	Q8IY17-4
	PNPLA6	NM_001166113.1		c.-118-5T>C		splice_region intron	N/A	NP_001159585.1	Q8IY17-2
	PNPLA6	NM_006702.5		c.-43+220T>C		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.-43+220T>C		intron	N/A	ENSP00000221249.5	Q8IY17-2
	PNPLA6	ENST00000450331.7	TSL:1	c.-118-5T>C		splice_region intron	N/A	ENSP00000394348.2	Q8IY17-2
	ENSG00000268614	ENST00000601870.1	TSL:4	n.*371+220T>C		intron	N/A	ENSP00000471492.1	M0R0W3

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5855 AN: 152044 Hom.: 299 Cov.: 32

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0999

Gnomad SAS AF: 0.0464

Gnomad FIN AF: 0.00830

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00616

Gnomad OTH AF: 0.0412

GnomAD4 exome AF: 0.0268 AC: 5037 AN: 187818 Hom.: 231 Cov.: 0 AF XY: 0.0278 AC XY: 2768 AN XY: 99590

African (AFR) AF: 0.0571 AC: 353 AN: 6180

American (AMR) AF: 0.166 AC: 1638 AN: 9896

Ashkenazi Jewish (ASJ) AF: 0.0229 AC: 115 AN: 5026

East Asian (EAS) AF: 0.0891 AC: 888 AN: 9970

South Asian (SAS) AF: 0.0379 AC: 1124 AN: 29672

European-Finnish (FIN) AF: 0.00769 AC: 72 AN: 9366

Middle Eastern (MID) AF: 0.0198 AC: 14 AN: 706

European-Non Finnish (NFE) AF: 0.00586 AC: 628 AN: 107110

Other (OTH) AF: 0.0207 AC: 205 AN: 9892

GnomAD4 genome AF: 0.0385 AC: 5858 AN: 152162 Hom.: 300 Cov.: 32 AF XY: 0.0409 AC XY: 3043 AN XY: 74384

African (AFR) AF: 0.0588 AC: 2443 AN: 41518

American (AMR) AF: 0.131 AC: 1998 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3468

East Asian (EAS) AF: 0.100 AC: 516 AN: 5162

South Asian (SAS) AF: 0.0462 AC: 223 AN: 4822

European-Finnish (FIN) AF: 0.00830 AC: 88 AN: 10606

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00616 AC: 419 AN: 67992

Other (OTH) AF: 0.0403 AC: 85 AN: 2108

Alfa AF: 0.0235 Hom.: 18

Bravo AF: 0.0514

Asia WGS AF: 0.0700 AC: 243 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	-0.90
CADD	Benign	4.0
DANN	Benign	0.64
PhyloP100		-0.70
PromoterAI		0.055	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=83/17	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000073
dbscSNV1_RF	Benign	0.0
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: rs746130; hg19: chr19-7600008;