10-88740006-A-G

Variant names:

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

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>G​(p.Asp276Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D276V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LIPK NM_001080518.2 missense
• Clinical Significance: Not reported in ClinVar
• 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, 0.787

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>G	p.Asp276Gly	missense	Exon 8 of 10	NP_001073987.1	Q5VXJ0
	LIPK	NM_001378091.1		c.728A>G	p.Asp243Gly	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>G	p.Asp276Gly	missense	Exon 8 of 10	ENSP00000383900.1	Q5VXJ0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000110 AC: 138 AN: 1255652 Hom.: 0 Cov.: 28 AF XY: 0.0000984 AC XY: 62 AN XY: 630274

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

African (AFR) AF: 0.00 AC: 0 AN: 28846

American (AMR) AF: 0.0000705 AC: 3 AN: 42578

Ashkenazi Jewish (ASJ) AF: 0.000222 AC: 5 AN: 22508

East Asian (EAS) AF: 0.000116 AC: 4 AN: 34426

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82464

European-Finnish (FIN) AF: 0.000699 AC: 32 AN: 45760

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5128

European-Non Finnish (NFE) AF: 0.0000912 AC: 86 AN: 942996

Other (OTH) AF: 0.000137 AC: 7 AN: 50946

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.9
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.063	T
Polyphen		1.0	D
Vest4		0.67
MutPred		0.56		Gain of catalytic residue at V277 (P = 0.0652)
MVP		0.89
MPC		0.040
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.69
gMVP		0.70
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.30		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;