ENST00000221249.10:c.-96A>C

Variant names:

• chr19-7534849-A-C
• rs604959
• ENST00000221249.10:c.-96A>C

Variant summary

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

The ENST00000221249.10(PNPLA6):​c.-96A>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 0.277 in 153,734 control chromosomes in the GnomAD database, including 6,013 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (5965 hom., cov: 32)
  • Exomes 𝑓: 0.22 (48 hom.)
• Consequence: PNPLA6 ENST00000221249.10 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.105
• Publications: 11 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=-0.85).
• BP6: Variant 19-7534849-A-C is Benign according to our data. Variant chr19-7534849-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 330509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

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.-96A>C		5_prime_UTR	Exon 1 of 34	NP_001159583.1	Q8IY17-4
	PNPLA6	NM_001166113.1		c.-172A>C		5_prime_UTR	Exon 1 of 35	NP_001159585.1	Q8IY17-2
	PNPLA6	NM_006702.5		c.-96A>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.-96A>C		5_prime_UTR	Exon 2 of 35	ENSP00000221249.5	Q8IY17-2
	PNPLA6	ENST00000450331.7	TSL:1	c.-172A>C		5_prime_UTR	Exon 1 of 35	ENSP00000394348.2	Q8IY17-2
	ENSG00000268614	ENST00000601870.1	TSL:4	n.*318A>C		non_coding_transcript_exon	Exon 5 of 10	ENSP00000471492.1	M0R0W3

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42098 AN: 151914 Hom.: 5945 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.240

GnomAD4 exome AF: 0.216 AC: 367 AN: 1702 Hom.: 48 Cov.: 0 AF XY: 0.209 AC XY: 203 AN XY: 972

African (AFR) AF: 0.200 AC: 2 AN: 10

American (AMR) AF: 0.259 AC: 85 AN: 328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8

East Asian (EAS) AF: 0.318 AC: 7 AN: 22

South Asian (SAS) AF: 0.181 AC: 55 AN: 304

European-Finnish (FIN) AF: 0.0833 AC: 1 AN: 12

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.210 AC: 202 AN: 962

Other (OTH) AF: 0.278 AC: 15 AN: 54

GnomAD4 genome AF: 0.277 AC: 42153 AN: 152032 Hom.: 5965 Cov.: 32 AF XY: 0.275 AC XY: 20430 AN XY: 74320

African (AFR) AF: 0.285 AC: 11832 AN: 41460

American (AMR) AF: 0.296 AC: 4524 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 579 AN: 3472

East Asian (EAS) AF: 0.291 AC: 1501 AN: 5160

South Asian (SAS) AF: 0.232 AC: 1120 AN: 4820

European-Finnish (FIN) AF: 0.308 AC: 3260 AN: 10586

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.273 AC: 18576 AN: 67942

Other (OTH) AF: 0.240 AC: 507 AN: 2112

Alfa AF: 0.271 Hom.: 19029

Bravo AF: 0.278

Asia WGS AF: 0.294 AC: 1021 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia 39 (1)
-	-	1	Mucolipidosis type IV (1)
-	-	1	Spastic Paraplegia, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.8
DANN	Benign	0.57
PhyloP100		-0.10
PromoterAI		-0.042	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs604959; hg19: chr19-7599735;