19-7561524-C-T

Variant names:

• chr19-7561524-C-T
• rs150392453
• NM_001166114.2:c.4060C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001166111.2(PNPLA6):​c.4090C>T​(p.Leu1364Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000328 in 1,608,852 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: PNPLA6 NM_001166111.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.66
• 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: 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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-7561524-C-T is Benign according to our data. Variant chr19-7561524-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 513833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.66 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0018 (274/152316) while in subpopulation AFR AF = 0.00616 (256/41574). AF 95% confidence interval is 0.00554. There are 1 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166111.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA6	NM_001166114.2	MANE Select	c.4060C>T	p.Leu1354Leu	synonymous	Exon 32 of 32	NP_001159586.1
	PNPLA6	NM_001166111.2		c.4090C>T	p.Leu1364Leu	synonymous	Exon 34 of 34	NP_001159583.1
	PNPLA6	NM_001166113.1		c.3946C>T	p.Leu1316Leu	synonymous	Exon 35 of 35	NP_001159585.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA6	ENST00000600737.6	TSL:1 MANE Select	c.4060C>T	p.Leu1354Leu	synonymous	Exon 32 of 32	ENSP00000473211.1
	PNPLA6	ENST00000221249.10	TSL:1	c.3946C>T	p.Leu1316Leu	synonymous	Exon 35 of 35	ENSP00000221249.5
	PNPLA6	ENST00000450331.7	TSL:1	c.3946C>T	p.Leu1316Leu	synonymous	Exon 35 of 35	ENSP00000394348.2

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 273 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00615

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000363 AC: 86 AN: 236928 AF XY: 0.000256

Gnomad AFR exome AF: 0.00547

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000174 AC: 254 AN: 1456536 Hom.: 0 Cov.: 32 AF XY: 0.000138 AC XY: 100 AN XY: 724046

African (AFR) AF: 0.00650 AC: 217 AN: 33400

American (AMR) AF: 0.000249 AC: 11 AN: 44216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39522

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5248

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110414

Other (OTH) AF: 0.000350 AC: 21 AN: 60078

GnomAD4 genome AF: 0.00180 AC: 274 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74480

African (AFR) AF: 0.00616 AC: 256 AN: 41574

American (AMR) AF: 0.000915 AC: 14 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.00223

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hereditary spastic paraplegia 39 (1)
-	-	1	PNPLA6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.2
DANN	Benign	0.62
PhyloP100		-1.7

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: rs150392453; hg19: chr19-7626410;