21-14144737-A-T

Position:

• chr21-14144737-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001302998.2(LIPI):​c.1181T>A​(p.Phe394Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LIPI NM_001302998.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29363263).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIPI	NM_001302998.2	c.1181T>A	p.Phe394Tyr	missense_variant	9/10	ENST00000681601.1	NP_001289927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIPI	ENST00000681601.1	c.1181T>A	p.Phe394Tyr	missense_variant	9/10		NM_001302998.2	ENSP00000505323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2024

The c.1244T>A (p.F415Y) alteration is located in exon 9 (coding exon 9) of the LIPI gene. This alteration results from a T to A substitution at nucleotide position 1244, causing the phenylalanine (F) at amino acid position 415 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	0.16
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.55	T;T;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Uncertain	-0.27	T
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N;.;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0040	D;.;.
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.93	P;.;.
Vest4		0.20
MutPred		0.56		Gain of sheet (P = 0.0221);.;.;
MVP		0.84
MPC		0.046
ClinPred		0.60	D
GERP RS		5.2
gMVP		0.51

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-15517058;