rs10947600

chr6-36301826-G-Achr6-36301826-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001374623.1(PNPLA1):c.776-35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 1,587,868 control chromosomes in the GnomAD database, including 133,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9962 hom., cov: 32)
  • Exomes 𝑓: 0.41 (123528 hom.)
• Consequence: PNPLA1 NM_001374623.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.134

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-36301826-G-A is Benign according to our data. Variant chr6-36301826-G-A is described in ClinVar as [Benign]. Clinvar id is 1287688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA1	NM_001374623.1	c.776-35G>A		intron_variant		ENST00000636260.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA1	ENST00000636260.2	c.776-35G>A		intron_variant		5	NM_001374623.1	A2

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49839 AN: 151982 Hom.: 9951 Cov.: 32

Gnomad AFR AF: 0.0994

Gnomad AMI AF: 0.538

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.271

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.278

GnomAD3 exomes AF: 0.391 AC: 92836 AN: 237148 Hom.: 20019 AF XY: 0.388 AC XY: 49532 AN XY: 127770

Gnomad AFR exome AF: 0.0889

Gnomad AMR exome AF: 0.554

Gnomad ASJ exome AF: 0.374

Gnomad EAS exome AF: 0.264

Gnomad SAS exome AF: 0.298

Gnomad FIN exome AF: 0.453

Gnomad NFE exome AF: 0.422

Gnomad OTH exome AF: 0.397

GnomAD4 exome AF: 0.407 AC: 584563 AN: 1435766 Hom.: 123528 Cov.: 38 AF XY: 0.403 AC XY: 286330 AN XY: 710544

Gnomad4 AFR exome AF: 0.0819

Gnomad4 AMR exome AF: 0.536

Gnomad4 ASJ exome AF: 0.374

Gnomad4 EAS exome AF: 0.289

Gnomad4 SAS exome AF: 0.299

Gnomad4 FIN exome AF: 0.449

Gnomad4 NFE exome AF: 0.426

Gnomad4 OTH exome AF: 0.369

GnomAD4 genome AF: 0.328 AC: 49859 AN: 152102 Hom.: 9962 Cov.: 32 AF XY: 0.331 AC XY: 24590 AN XY: 74348

Gnomad4 AFR AF: 0.0994

Gnomad4 AMR AF: 0.430

Gnomad4 ASJ AF: 0.365

Gnomad4 EAS AF: 0.271

Gnomad4 SAS AF: 0.283

Gnomad4 FIN AF: 0.461

Gnomad4 NFE AF: 0.429

Gnomad4 OTH AF: 0.274

Alfa AF: 0.394 Hom.: 23063

Bravo AF: 0.315

Asia WGS AF: 0.228 AC: 794 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Autosomal recessive congenital ichthyosis 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	4.1
Dann	Benign	0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs10947600; hg19: chr6-36269603; COSMIC: COSV57233271;