21-14189302-C-T

Variant names:

• chr21-14189302-C-T
• rs11909217
• NM_001302998.2:c.164G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000681601.1(LIPI):​c.164G>A​(p.Cys55Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00352 in 1,613,860 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (26 hom.)
• Consequence: LIPI ENST00000681601.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: 4.99
• Publications: 9 publications found

Genes affected

LIPI (HGNC:18821): (lipase I) The protein encoded by this gene is a phospholipase that hydrolyzes phosphatidic acid to produce lysophosphatidic acid. Defects in this gene are a cause of susceptibility to familial hypertrigliceridemia. This gene is also expressed at high levels in Ewing family tumor cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

LIPI Gene-Disease associations (from GenCC):

• hypertriglyceridemia

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014380097).
• BP6: Variant 21-14189302-C-T is Benign according to our data. Variant chr21-14189302-C-T is described in ClinVar as Benign. ClinVar VariationId is 1822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00712 (1084/152256) while in subpopulation AFR AF = 0.0178 (738/41560). AF 95% confidence interval is 0.0167. There are 11 homozygotes in GnomAd4. There are 527 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1084 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000681601.1. 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
	LIPI	NM_001302998.2	MANE Select	c.164G>A	p.Cys55Tyr	missense	Exon 2 of 10	NP_001289927.1
	LIPI	NM_001303000.2		c.164G>A	p.Cys55Tyr	missense	Exon 2 of 10	NP_001289929.1
	LIPI	NM_001302999.2		c.164G>A	p.Cys55Tyr	missense	Exon 2 of 9	NP_001289928.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPI	ENST00000681601.1	MANE Select	c.164G>A	p.Cys55Tyr	missense	Exon 2 of 10	ENSP00000505323.1
	LIPI	ENST00000536861.6	TSL:1	c.164G>A	p.Cys55Tyr	missense	Exon 2 of 10	ENSP00000440381.3
	LIPI	ENST00000614229.5	TSL:1	c.164G>A	p.Cys55Tyr	missense	Exon 2 of 9	ENSP00000482652.2

Frequencies

GnomAD3 genomes AF: 0.00712 AC: 1083 AN: 152138 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00244

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00472 AC: 1187 AN: 251350 AF XY: 0.00468

Gnomad AFR exome AF: 0.0203

Gnomad AMR exome AF: 0.00350

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00270

Gnomad OTH exome AF: 0.00636

GnomAD4 exome AF: 0.00315 AC: 4602 AN: 1461604 Hom.: 26 Cov.: 31 AF XY: 0.00326 AC XY: 2367 AN XY: 727108

African (AFR) AF: 0.0224 AC: 749 AN: 33470

American (AMR) AF: 0.00400 AC: 179 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 447 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00698 AC: 602 AN: 86250

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53418

Middle Eastern (MID) AF: 0.0108 AC: 62 AN: 5764

European-Non Finnish (NFE) AF: 0.00203 AC: 2262 AN: 1111794

Other (OTH) AF: 0.00494 AC: 298 AN: 60382

GnomAD4 genome AF: 0.00712 AC: 1084 AN: 152256 Hom.: 11 Cov.: 32 AF XY: 0.00708 AC XY: 527 AN XY: 74438

African (AFR) AF: 0.0178 AC: 738 AN: 41560

American (AMR) AF: 0.00477 AC: 73 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4822

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00244 AC: 166 AN: 68018

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.00440 Hom.: 16

Bravo AF: 0.00804

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.0191 AC: 84

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00492 AC: 597

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00327

EpiControl AF: 0.00379

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Hypertriglyceridemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.45	D
PhyloP100		5.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-11	D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MVP		0.79
MPC		0.16
ClinPred		0.062	T
GERP RS		5.3
gMVP		0.70
Mutation Taster		=69/31	polymorphism

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: rs11909217; hg19: chr21-15561623; COSMIC: COSV99064910; COSMIC: COSV99064910;