6-36270663-G-C

Variant names:

• chr6-36270663-G-C
• NM_001374623.1:c.204G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001374623.1(PNPLA1):​c.204G>C​(p.Met68Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PNPLA1 NM_001374623.1 missense, splice_region
• Scores: Splicing: ADA: 0.006462
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12

Genes affected

PNPLA1 (HGNC:21246): (patatin like phospholipase domain containing 1) The protein encoded by this gene belongs to the patatin-like phospholipase (PNPLA) family, which is characterized by the presence of a highly conserved patatin domain. PNPLA family members have diverse lipolytic and acyltransferase activities, and are key elements in lipid metabolism. While other members of this family have been well characterized, the function of this gene remained an enigma. However, recent studies show that this gene is expressed in the skin epidermal keratinocytes, and has a role in glycerophospholipid metabolism in the cutaneous barrier. Consistent with these observations, mutations in this gene are associated with ichthyosis in human (autosomal recessive congenital ichthyoses, ARCI) and dog. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16723084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA1	NM_001374623.1	c.204G>C	p.Met68Ile	missense_variant, splice_region_variant	Exon 1 of 9	ENST00000636260.2	NP_001361552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA1	ENST00000636260.2	c.204G>C	p.Met68Ile	missense_variant, splice_region_variant	Exon 1 of 9	5	NM_001374623.1	ENSP00000490785.2
PNPLA1	ENST00000457797.5	c.204G>C	p.Met68Ile	missense_variant, splice_region_variant	Exon 1 of 8	1		ENSP00000391868.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398196 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 689652

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 68 of the PNPLA1 protein (p.Met68Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PNPLA1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0023	.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.040
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.66	.;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.98	N;N
REVEL	Benign	0.16
Sift	Benign	0.24	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.28	.;B
Vest4		0.21
MutPred		0.56		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.74
MPC		0.77
ClinPred		0.81	D
GERP RS		4.5
Varity_R		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0065
dbscSNV1_RF	Benign	0.062
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-36238440;