6-36301826-G-A

Variant names:

• chr6-36301826-G-A
• rs10947600
• NM_001374623.1:c.776-35G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 publications found

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]

PNPLA1 Gene-Disease associations (from GenCC):

• autosomal recessive congenital ichthyosis 10

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P, Genomics England PanelApp
• congenital non-bullous ichthyosiform erythroderma

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374623.1. 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
	PNPLA1	NM_001374623.1	MANE Select	c.776-35G>A		intron	N/A	NP_001361552.1
	PNPLA1	NM_001145717.1		c.776-35G>A		intron	N/A	NP_001139189.2
	PNPLA1	NM_001145716.2		c.518-35G>A		intron	N/A	NP_001139188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA1	ENST00000636260.2	TSL:5 MANE Select	c.776-35G>A		intron	N/A	ENSP00000490785.2
	PNPLA1	ENST00000457797.5	TSL:1	c.779-35G>A		intron	N/A	ENSP00000391868.1
	PNPLA1	ENST00000394571.3	TSL:1	c.776-35G>A		intron	N/A	ENSP00000378072.2

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

GnomAD2 exomes AF: 0.391 AC: 92836 AN: 237148 AF XY: 0.388

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 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

African (AFR) AF: 0.0819 AC: 2702 AN: 32974

American (AMR) AF: 0.536 AC: 23044 AN: 43016

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 9183 AN: 24586

East Asian (EAS) AF: 0.289 AC: 11354 AN: 39342

South Asian (SAS) AF: 0.299 AC: 24681 AN: 82494

European-Finnish (FIN) AF: 0.449 AC: 23557 AN: 52478

Middle Eastern (MID) AF: 0.252 AC: 1429 AN: 5670

European-Non Finnish (NFE) AF: 0.426 AC: 466743 AN: 1096008

Other (OTH) AF: 0.369 AC: 21870 AN: 59198

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

African (AFR) AF: 0.0994 AC: 4125 AN: 41518

American (AMR) AF: 0.430 AC: 6582 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1268 AN: 3470

East Asian (EAS) AF: 0.271 AC: 1404 AN: 5184

South Asian (SAS) AF: 0.283 AC: 1366 AN: 4828

European-Finnish (FIN) AF: 0.461 AC: 4867 AN: 10550

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.429 AC: 29119 AN: 67950

Other (OTH) AF: 0.274 AC: 577 AN: 2108

Alfa AF: 0.382 Hom.: 35093

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

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive congenital ichthyosis 10 Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.1
DANN	Benign	0.23
PhyloP100		0.13
Mutation Taster		=100/0	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: rs10947600; hg19: chr6-36269603; COSMIC: COSV57233271;