chr3-185514509-A-G

Variant names:

• chr3-185514509-A-G
• rs756417269
• NM_139248.3:c.995T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_139248.3(LIPH):​c.995T>C​(p.Phe332Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000694 in 1,296,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: LIPH NM_139248.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80
• Publications: 0 publications found

Genes affected

LIPH (HGNC:18483): (lipase H) This gene encodes a membrane-bound member of the mammalian triglyceride lipase family. It catalyzes the production of 2-acyl lysophosphatidic acid (LPA), which is a lipid mediator with diverse biological properties that include platelet aggregation, smooth muscle contraction, and stimulation of cell proliferation and motility. [provided by RefSeq, Jul 2008]

LIPH Gene-Disease associations (from GenCC):

• hypotrichosis 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hypotrichosis simplex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated familial wooly hair disorder

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TMEM41A-DT (HGNC:58335):

ENSG00000309120 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25784335).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139248.3. 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
	LIPH	NM_139248.3	MANE Select	c.995T>C	p.Phe332Ser	missense	Exon 8 of 10	NP_640341.1	Q8WWY8
	LIPH	NM_001438651.1		c.905T>C	p.Phe302Ser	missense	Exon 7 of 9	NP_001425580.1
	LIPH	NM_001438029.1		c.893T>C	p.Phe298Ser	missense	Exon 7 of 9	NP_001424958.1	A2IBA6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPH	ENST00000296252.9	TSL:1 MANE Select	c.995T>C	p.Phe332Ser	missense	Exon 8 of 10	ENSP00000296252.4	Q8WWY8
	LIPH	ENST00000424591.6	TSL:1	c.893T>C	p.Phe298Ser	missense	Exon 7 of 9	ENSP00000396384.2	A2IBA6
	LIPH	ENST00000953488.1		c.1016T>C	p.Phe339Ser	missense	Exon 8 of 10	ENSP00000623547.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 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: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251350 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000699 AC: 8 AN: 1144528 Hom.: 0 Cov.: 18 AF XY: 0.0000137 AC XY: 8 AN XY: 584316

African (AFR) AF: 0.00 AC: 0 AN: 27432

American (AMR) AF: 0.00 AC: 0 AN: 44342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24106

East Asian (EAS) AF: 0.000131 AC: 5 AN: 38266

South Asian (SAS) AF: 0.00 AC: 0 AN: 79916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5202

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 822176

Other (OTH) AF: 0.0000401 AC: 2 AN: 49860

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15260

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

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.041
Eigen_PC	Benign	0.021
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.61
Sift	Benign	0.25	T
Sift4G	Benign	0.29	T
Polyphen		0.080	B
Vest4		0.45
MutPred		0.58		Loss of stability (P = 0.0698)
MVP		0.86
MPC		0.22
ClinPred		0.62	D
GERP RS		4.9
Varity_R		0.20
gMVP		0.78
Mutation Taster		=73/27	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: rs756417269; hg19: chr3-185232297; COSMIC: COSV105893639; COSMIC: COSV105893639;