chr6-36302353-C-A

Variant names:

• chr6-36302353-C-A
• rs12199580
• NM_001374623.1:c.1268C>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.1268C>A​(p.Pro423His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 1,611,662 control chromosomes in the GnomAD database, including 137,027 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10605 hom., cov: 32)
  • Exomes 𝑓: 0.41 (126422 hom.)
• Consequence: PNPLA1 NM_001374623.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.183
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.4265744E-5).
• BP6: Variant 6-36302353-C-A is Benign according to our data. Variant chr6-36302353-C-A is described in ClinVar as Benign. ClinVar VariationId is 257569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.43 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA1	NM_001374623.1	MANE Select	c.1268C>A	p.Pro423His	missense	Exon 6 of 9	NP_001361552.1	A0A1B0GW56
	PNPLA1	NM_001145717.1		c.1268C>A	p.Pro423His	missense	Exon 6 of 8	NP_001139189.2	Q8N8W4-1
	PNPLA1	NM_001145716.2		c.1010C>A	p.Pro337His	missense	Exon 6 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.1268C>A	p.Pro423His	missense	Exon 6 of 9	ENSP00000490785.2	A0A1B0GW56
	PNPLA1	ENST00000457797.5	TSL:1	c.1271C>A	p.Pro424His	missense	Exon 6 of 8	ENSP00000391868.1	A0A0C4DG24
	PNPLA1	ENST00000394571.3	TSL:1	c.1268C>A	p.Pro423His	missense	Exon 6 of 8	ENSP00000378072.2	Q8N8W4-1

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53841 AN: 151930 Hom.: 10592 Cov.: 32

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.539

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.367

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.308

GnomAD2 exomes AF: 0.396 AC: 98668 AN: 249434 AF XY: 0.390

Gnomad AFR exome AF: 0.194

Gnomad AMR exome AF: 0.563

Gnomad ASJ exome AF: 0.380

Gnomad EAS exome AF: 0.187

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.422

Gnomad OTH exome AF: 0.400

GnomAD4 exome AF: 0.409 AC: 597541 AN: 1459614 Hom.: 126422 Cov.: 73 AF XY: 0.405 AC XY: 294166 AN XY: 725760

African (AFR) AF: 0.183 AC: 6121 AN: 33456

American (AMR) AF: 0.547 AC: 24432 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 9830 AN: 25968

East Asian (EAS) AF: 0.207 AC: 8196 AN: 39656

South Asian (SAS) AF: 0.308 AC: 26498 AN: 86120

European-Finnish (FIN) AF: 0.443 AC: 23614 AN: 53272

Middle Eastern (MID) AF: 0.263 AC: 1516 AN: 5756

European-Non Finnish (NFE) AF: 0.428 AC: 474727 AN: 1110446

Other (OTH) AF: 0.375 AC: 22607 AN: 60292

GnomAD4 genome AF: 0.354 AC: 53893 AN: 152048 Hom.: 10605 Cov.: 32 AF XY: 0.356 AC XY: 26489 AN XY: 74314

African (AFR) AF: 0.200 AC: 8292 AN: 41474

American (AMR) AF: 0.439 AC: 6710 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 1273 AN: 3466

East Asian (EAS) AF: 0.194 AC: 998 AN: 5156

South Asian (SAS) AF: 0.289 AC: 1393 AN: 4818

European-Finnish (FIN) AF: 0.454 AC: 4796 AN: 10564

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.430 AC: 29236 AN: 67956

Other (OTH) AF: 0.303 AC: 641 AN: 2116

Alfa AF: 0.397 Hom.: 42359

Bravo AF: 0.347

TwinsUK AF: 0.424 AC: 1573

ALSPAC AF: 0.427 AC: 1644

ESP6500AA AF: 0.207 AC: 913

ESP6500EA AF: 0.433 AC: 3723

ExAC AF: 0.385 AC: 46774

Asia WGS AF: 0.218 AC: 760 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Autosomal recessive congenital ichthyosis 10 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.0059	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.000034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.18
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.033
Sift	Benign	0.14	T
Sift4G	Benign	0.34	T
Polyphen		0.043	B
Vest4		0.083
MPC		0.24
ClinPred		0.0029	T
GERP RS		1.7
Varity_R		0.054
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: rs12199580; hg19: chr6-36270130; COSMIC: COSV57233066;