chr6-36293137-C-T

Variant names:

• chr6-36293137-C-T
• rs2239796
• NM_001374623.1:c.504+11C>T

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.504+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 1,612,660 control chromosomes in the GnomAD database, including 80,954 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6015 hom., cov: 32)
  • Exomes 𝑓: 0.31 (74939 hom.)
• Consequence: PNPLA1 NM_001374623.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.29
• Publications: 9 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=-0.84).
• BP6: Variant 6-36293137-C-T is Benign according to our data. Variant chr6-36293137-C-T is described in ClinVar as Benign. ClinVar VariationId is 257573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.355 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.504+11C>T		intron	N/A	NP_001361552.1
	PNPLA1	NM_001145717.1		c.504+11C>T		intron	N/A	NP_001139189.2
	PNPLA1	NM_001145716.2		c.219+11C>T		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.504+11C>T		intron	N/A	ENSP00000490785.2
	PNPLA1	ENST00000457797.5	TSL:1	c.507+11C>T		intron	N/A	ENSP00000391868.1
	PNPLA1	ENST00000394571.3	TSL:1	c.504+11C>T		intron	N/A	ENSP00000378072.2

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38192 AN: 151966 Hom.: 6002 Cov.: 32

Gnomad AFR AF: 0.0647

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.210

GnomAD2 exomes AF: 0.320 AC: 80234 AN: 250984 AF XY: 0.314

Gnomad AFR exome AF: 0.0584

Gnomad AMR exome AF: 0.520

Gnomad ASJ exome AF: 0.232

Gnomad EAS exome AF: 0.286

Gnomad FIN exome AF: 0.378

Gnomad NFE exome AF: 0.315

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.313 AC: 456477 AN: 1460574 Hom.: 74939 Cov.: 37 AF XY: 0.310 AC XY: 224948 AN XY: 726670

African (AFR) AF: 0.0501 AC: 1676 AN: 33452

American (AMR) AF: 0.497 AC: 22211 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 6000 AN: 26110

East Asian (EAS) AF: 0.313 AC: 12434 AN: 39686

South Asian (SAS) AF: 0.263 AC: 22653 AN: 86232

European-Finnish (FIN) AF: 0.376 AC: 20088 AN: 53392

Middle Eastern (MID) AF: 0.192 AC: 1105 AN: 5764

European-Non Finnish (NFE) AF: 0.318 AC: 353528 AN: 1110902

Other (OTH) AF: 0.278 AC: 16782 AN: 60352

GnomAD4 genome AF: 0.251 AC: 38207 AN: 152086 Hom.: 6015 Cov.: 32 AF XY: 0.256 AC XY: 19059 AN XY: 74344

African (AFR) AF: 0.0645 AC: 2680 AN: 41540

American (AMR) AF: 0.363 AC: 5554 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 757 AN: 3466

East Asian (EAS) AF: 0.299 AC: 1547 AN: 5172

South Asian (SAS) AF: 0.250 AC: 1205 AN: 4822

European-Finnish (FIN) AF: 0.384 AC: 4053 AN: 10546

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.319 AC: 21699 AN: 67942

Other (OTH) AF: 0.207 AC: 436 AN: 2108

Alfa AF: 0.298 Hom.: 7635

Bravo AF: 0.242

Asia WGS AF: 0.212 AC: 736 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Autosomal recessive congenital ichthyosis 10 (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.11
DANN	Benign	0.43
PhyloP100		-4.3
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: rs2239796; hg19: chr6-36260914; COSMIC: COSV57233262;