chr6-36306376-C-T

Variant names:

• chr6-36306376-C-T
• rs12197079
• NM_001374623.1:c.1469C>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.1469C>T​(p.Thr490Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 1,605,392 control chromosomes in the GnomAD database, including 65,828 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6405 hom., cov: 32)
  • Exomes 𝑓: 0.28 (59423 hom.)
• Consequence: PNPLA1 NM_001374623.1 missense, splice_region
• Scores: Splicing: ADA: 0.0009790
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.41
• Publications: 29 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 (MetaRNN=0.003913671).
• BP6: Variant 6-36306376-C-T is Benign according to our data. Variant chr6-36306376-C-T is described in ClinVar as Benign. ClinVar VariationId is 257570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.316 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.1469C>T	p.Thr490Met	missense splice_region	Exon 7 of 9	NP_001361552.1
	PNPLA1	NM_001145717.1		c.1469C>T	p.Thr490Met	missense splice_region	Exon 7 of 8	NP_001139189.2
	PNPLA1	NM_001145716.2		c.1211C>T	p.Thr404Met	missense splice_region	Exon 7 of 8	NP_001139188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA1	ENST00000636260.2	TSL:5 MANE Select	c.1469C>T	p.Thr490Met	missense splice_region	Exon 7 of 9	ENSP00000490785.2
	PNPLA1	ENST00000457797.5	TSL:1	c.1472C>T	p.Thr491Met	missense splice_region	Exon 7 of 8	ENSP00000391868.1
	PNPLA1	ENST00000394571.3	TSL:1	c.1469C>T	p.Thr490Met	missense splice_region	Exon 7 of 8	ENSP00000378072.2

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43089 AN: 151974 Hom.: 6397 Cov.: 32

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.0850

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.309

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.280

GnomAD2 exomes AF: 0.258 AC: 62996 AN: 244034 AF XY: 0.263

Gnomad AFR exome AF: 0.318

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.246

Gnomad EAS exome AF: 0.0827

Gnomad FIN exome AF: 0.309

Gnomad NFE exome AF: 0.291

Gnomad OTH exome AF: 0.264

GnomAD4 exome AF: 0.282 AC: 409646 AN: 1453298 Hom.: 59423 Cov.: 32 AF XY: 0.282 AC XY: 204099 AN XY: 723150

African (AFR) AF: 0.322 AC: 10590 AN: 32872

American (AMR) AF: 0.168 AC: 7234 AN: 42932

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 6435 AN: 25860

East Asian (EAS) AF: 0.0802 AC: 3170 AN: 39526

South Asian (SAS) AF: 0.277 AC: 23528 AN: 84808

European-Finnish (FIN) AF: 0.309 AC: 16479 AN: 53296

Middle Eastern (MID) AF: 0.342 AC: 1952 AN: 5708

European-Non Finnish (NFE) AF: 0.292 AC: 323845 AN: 1108338

Other (OTH) AF: 0.274 AC: 16413 AN: 59958

GnomAD4 genome AF: 0.284 AC: 43129 AN: 152094 Hom.: 6405 Cov.: 32 AF XY: 0.281 AC XY: 20870 AN XY: 74336

African (AFR) AF: 0.321 AC: 13295 AN: 41470

American (AMR) AF: 0.203 AC: 3098 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 834 AN: 3470

East Asian (EAS) AF: 0.0856 AC: 444 AN: 5186

South Asian (SAS) AF: 0.269 AC: 1297 AN: 4824

European-Finnish (FIN) AF: 0.302 AC: 3193 AN: 10578

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20035 AN: 67988

Other (OTH) AF: 0.280 AC: 591 AN: 2114

Alfa AF: 0.288 Hom.: 25968

Bravo AF: 0.279

TwinsUK AF: 0.299 AC: 1107

ALSPAC AF: 0.285 AC: 1100

ESP6500AA AF: 0.318 AC: 1401

ESP6500EA AF: 0.287 AC: 2464

ExAC AF: 0.263 AC: 31867

EpiCase AF: 0.294

EpiControl AF: 0.285

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)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.010
DANN	Benign	0.86
DEOGEN2	Benign	0.00080	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.17	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	N
PhyloP100		-3.4
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.63	N
REVEL	Benign	0.011
Sift	Benign	1.0	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.043
MPC		0.21
ClinPred		0.0027	T
GERP RS		-3.4
Varity_R		0.019
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00098
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.040		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: rs12197079; hg19: chr6-36274153; COSMIC: COSV57237701;