10-88740006-A-T

Variant names:

• chr10-88740006-A-T
• rs1026958957
• NM_001080518.2:c.827A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001080518.2(LIPK):​c.827A>T​(p.Asp276Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 151,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LIPK NM_001080518.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.92
• Publications: 0 publications found

Genes affected

LIPK (HGNC:23444): (lipase family member K) Predicted to enable lipoprotein lipase activity. Predicted to be involved in cornification. Predicted to be located in extracellular region. Predicted to be active in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080518.2. 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
	LIPK	NM_001080518.2	MANE Select	c.827A>T	p.Asp276Val	missense	Exon 8 of 10	NP_001073987.1	Q5VXJ0
	LIPK	NM_001378091.1		c.728A>T	p.Asp243Val	missense	Exon 9 of 11	NP_001365020.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPK	ENST00000404190.3	TSL:1 MANE Select	c.827A>T	p.Asp276Val	missense	Exon 8 of 10	ENSP00000383900.1	Q5VXJ0

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150880 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248690 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00102 AC: 1282 AN: 1253144 Hom.: 0 Cov.: 28 AF XY: 0.000952 AC XY: 599 AN XY: 629102

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000625 AC: 18 AN: 28800

American (AMR) AF: 0.000211 AC: 9 AN: 42558

Ashkenazi Jewish (ASJ) AF: 0.000978 AC: 22 AN: 22484

East Asian (EAS) AF: 0.000698 AC: 24 AN: 34386

South Asian (SAS) AF: 0.000291 AC: 24 AN: 82424

European-Finnish (FIN) AF: 0.000196 AC: 9 AN: 45810

Middle Eastern (MID) AF: 0.000978 AC: 5 AN: 5110

European-Non Finnish (NFE) AF: 0.00121 AC: 1134 AN: 940714

Other (OTH) AF: 0.000728 AC: 37 AN: 50858

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151014 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73798

African (AFR) AF: 0.00 AC: 0 AN: 41290

American (AMR) AF: 0.00 AC: 0 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 4952

South Asian (SAS) AF: 0.00 AC: 0 AN: 4516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10538

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

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67776

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.0000548

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.082	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		5.9
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.61		Loss of methylation at R274 (P = 0.0697)
MVP		0.91
MPC		0.039
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.75
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.29		Position offset: -10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1026958957; hg19: chr10-90499763;