NM_001166114.2:c.3095G>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM1PP2BP4_Strong

The NM_001166114.2(PNPLA6):c.3095G>C(p.Ser1032Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000368 in 1,602,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

PNPLA6
NM_001166114.2 missense, splice_region

Scores

Splicing: ADA: 0.00001767

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: -0.122

Publications

1 publications found

Variant links:

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: Orphanet, Labcorp Genetics (formerly Invitae)
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

PNPLA6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001166114.2

PP2

Missense variant in the PNPLA6 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 4.3547 (above the threshold of 3.09). Trascript score misZ: 3.5139 (above the threshold of 3.09). GenCC associations: The gene is linked to retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome, cerebellar ataxia-hypogonadism syndrome, PNPLA6-related spastic paraplegia with or without ataxia, ataxia-hypogonadism-choroidal dystrophy syndrome, trichomegaly-retina pigmentary degeneration-dwarfism syndrome, hereditary spastic paraplegia 39, Laurence-Moon syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.044030935).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166114.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNPLA6	NM_001166114.2	MANE Select	c.3095G>C	p.Ser1032Thr	missense splice_region	Exon 25 of 32	NP_001159586.1	A0A384DVU0
PNPLA6	NM_001166111.2		c.3125G>C	p.Ser1042Thr	missense splice_region	Exon 27 of 34	NP_001159583.1	Q8IY17-4
PNPLA6	NM_001166113.1		c.2981G>C	p.Ser994Thr	missense splice_region	Exon 28 of 35	NP_001159585.1	Q8IY17-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNPLA6	ENST00000600737.6	TSL:1 MANE Select	c.3095G>C	p.Ser1032Thr	missense splice_region	Exon 25 of 32	ENSP00000473211.1	A0A384DVU0
PNPLA6	ENST00000221249.10	TSL:1	c.2981G>C	p.Ser994Thr	missense splice_region	Exon 28 of 35	ENSP00000221249.5	Q8IY17-2
PNPLA6	ENST00000450331.7	TSL:1	c.2981G>C	p.Ser994Thr	missense splice_region	Exon 28 of 35	ENSP00000394348.2	Q8IY17-2

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251478

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000324

AC:

AN:

1449960

Hom.:

Cov.:

AF XY:

0.0000180

AC XY:

AN XY:

722062

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33250

American (AMR)

AF:

0.0000224

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26066

East Asian (EAS)

AF:

0.000151

AC:

AN:

39652

South Asian (SAS)

AF:

0.00

AC:

AN:

86000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00000272

AC:

AN:

1101168

Other (OTH)

AF:

0.000617

AC:

AN:

59970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41510

American (AMR)

AF:

0.000458

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000225

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 39 (2)

Inborn genetic diseases (1)

Laurence-Moon syndrome;C1848745:Trichomegaly-retina pigmentary degeneration-dwarfism syndrome;C1859093:Ataxia-hypogonadism-choroidal dystrophy syndrome;C2677586:Hereditary spastic paraplegia 39 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.51

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.81

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.85

M_CAP

Benign

0.062

MetaRNN

Benign

0.044

MetaSVM

Benign

-0.85

PhyloP100

-0.12

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.3

REVEL

Benign

0.072

Sift

Benign

0.27

Sift4G

Benign

0.42

Polyphen

0.0070

Vest4

0.22

MVP

0.40

MPC

0.85

ClinPred

0.033

GERP RS

1.4

Varity_R

0.045

gMVP

0.50

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000018

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over