10-88762210-G-A

Variant names:

• chr10-88762210-G-A
• rs1375369840
• NM_001102469.2:c.131G>A

Variant summary

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

The NM_001102469.2(LIPN):​c.131G>A​(p.Gly44Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,450,414 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G44A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LIPN NM_001102469.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.03
• Publications: 0 publications found

Genes affected

LIPN (HGNC:23452): (lipase family member N) The gene encodes a lipase that is highly expressed in granular keratinocytes in the epidermis, and plays a role in the differentiation of keratinocytes. Mutations in this gene are associated with lamellar ichthyosis type 4. [provided by RefSeq, Dec 2011]

LIPN Gene-Disease associations (from GenCC):

• autosomal recessive congenital ichthyosis 8

  Inheritance: Unknown, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• lamellar ichthyosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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, 0.746

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001102469.2. 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
	LIPN	NM_001102469.2	MANE Select	c.131G>A	p.Gly44Asp	missense	Exon 3 of 10	NP_001095939.1	Q5VXI9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPN	ENST00000404459.2	TSL:1 MANE Select	c.131G>A	p.Gly44Asp	missense	Exon 3 of 10	ENSP00000383923.1	Q5VXI9
	LIPN	ENST00000674982.1		n.264G>A		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450414 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 721390

African (AFR) AF: 0.00 AC: 0 AN: 33262

American (AMR) AF: 0.00 AC: 0 AN: 44016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25958

East Asian (EAS) AF: 0.00 AC: 0 AN: 39356

South Asian (SAS) AF: 0.00 AC: 0 AN: 84940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53096

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104108

Other (OTH) AF: 0.00 AC: 0 AN: 59934

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.73		Gain of catalytic residue at G44 (P = 0.0466)
MVP		0.98
MPC		0.13
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.84
gMVP		0.77
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1375369840; hg19: chr10-90521967;