rs45621032

Variant names:

• chr6-36306371-T-A
• rs45621032
• NM_001374623.1:c.1464T>A

Your query was ambiguous. Multiple possible variants found:

• chr6-36306371-T-A
• chr6-36306371-T-G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BS1 BS2

The NM_001374623.1(PNPLA1):​c.1464T>A​(p.Tyr488*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,610,946 control chromosomes in the GnomAD database, including 243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.011 (15 hom., cov: 31)
  • Exomes 𝑓: 0.016 (228 hom.)
• Consequence: PNPLA1 NM_001374623.1 stop_gained
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -5.48
• Publications: 19 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• congenital non-bullous ichthyosiform erythroderma

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 6-36306371-T-A is Benign according to our data. Variant chr6-36306371-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0111 (1696/152274) while in subpopulation NFE AF = 0.018 (1224/68026). AF 95% confidence interval is 0.0172. There are 15 homozygotes in GnomAd4. There are 776 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA1	NM_001374623.1	MANE Select	c.1464T>A	p.Tyr488*	stop_gained	Exon 7 of 9	NP_001361552.1	A0A1B0GW56
	PNPLA1	NM_001145717.1		c.1464T>A	p.Tyr488*	stop_gained	Exon 7 of 8	NP_001139189.2	Q8N8W4-1
	PNPLA1	NM_001145716.2		c.1206T>A	p.Tyr402*	stop_gained	Exon 7 of 8	NP_001139188.1	Q8N8W4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA1	ENST00000636260.2	TSL:5 MANE Select	c.1464T>A	p.Tyr488*	stop_gained	Exon 7 of 9	ENSP00000490785.2	A0A1B0GW56
	PNPLA1	ENST00000457797.5	TSL:1	c.1467T>A	p.Tyr489*	stop_gained	Exon 7 of 8	ENSP00000391868.1	A0A0C4DG24
	PNPLA1	ENST00000394571.3	TSL:1	c.1464T>A	p.Tyr488*	stop_gained	Exon 7 of 8	ENSP00000378072.2	Q8N8W4-1

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1697 AN: 152156 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0116 AC: 2887 AN: 247820 AF XY: 0.0121

Gnomad AFR exome AF: 0.00236

Gnomad AMR exome AF: 0.00997

Gnomad ASJ exome AF: 0.0162

Gnomad EAS exome AF: 0.00139

Gnomad FIN exome AF: 0.00440

Gnomad NFE exome AF: 0.0182

Gnomad OTH exome AF: 0.0133

GnomAD4 exome AF: 0.0159 AC: 23196 AN: 1458672 Hom.: 228 Cov.: 30 AF XY: 0.0155 AC XY: 11224 AN XY: 725726

African (AFR) AF: 0.00262 AC: 87 AN: 33240

American (AMR) AF: 0.0107 AC: 470 AN: 43894

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 419 AN: 26032

East Asian (EAS) AF: 0.000833 AC: 33 AN: 39602

South Asian (SAS) AF: 0.00336 AC: 288 AN: 85676

European-Finnish (FIN) AF: 0.00405 AC: 216 AN: 53384

Middle Eastern (MID) AF: 0.0103 AC: 59 AN: 5742

European-Non Finnish (NFE) AF: 0.0187 AC: 20743 AN: 1110900

Other (OTH) AF: 0.0146 AC: 881 AN: 60202

GnomAD4 genome AF: 0.0111 AC: 1696 AN: 152274 Hom.: 15 Cov.: 31 AF XY: 0.0104 AC XY: 776 AN XY: 74448

African (AFR) AF: 0.00284 AC: 118 AN: 41568

American (AMR) AF: 0.0138 AC: 211 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4822

European-Finnish (FIN) AF: 0.00386 AC: 41 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0180 AC: 1224 AN: 68026

Other (OTH) AF: 0.0170 AC: 36 AN: 2116

Alfa AF: 0.0161 Hom.: 18

Bravo AF: 0.0123

TwinsUK AF: 0.0205 AC: 76

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0148 AC: 127

ExAC AF: 0.0114 AC: 1379

Asia WGS AF: 0.00375 AC: 14 AN: 3478

EpiCase AF: 0.0200

EpiControl AF: 0.0201

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Autosomal recessive congenital ichthyosis 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Benign	0.88
Eigen	Benign	-0.70
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0060	N
PhyloP100		-5.5
Vest4		0.26
GERP RS		-8.3
Mutation Taster		=197/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs45621032; hg19: chr6-36274148;