3-185519286-G-T
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong
The NM_139248.3(LIPH):c.742C>A(p.His248Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,100 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 Likely pathogenic (★★).
Frequency
Consequence
NM_139248.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LIPH | NM_139248.3 | c.742C>A | p.His248Asn | missense_variant | Exon 6 of 10 | ENST00000296252.9 | NP_640341.1 | |
LIPH | XM_006713529.5 | c.652C>A | p.His218Asn | missense_variant | Exon 5 of 9 | XP_006713592.1 | ||
LIPH | XM_017005852.3 | c.640C>A | p.His214Asn | missense_variant | Exon 5 of 9 | XP_016861341.1 | ||
LIPH | XM_011512530.4 | c.613C>A | p.His205Asn | missense_variant | Exon 7 of 11 | XP_011510832.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LIPH | ENST00000296252.9 | c.742C>A | p.His248Asn | missense_variant | Exon 6 of 10 | 1 | NM_139248.3 | ENSP00000296252.4 | ||
LIPH | ENST00000424591.6 | c.640C>A | p.His214Asn | missense_variant | Exon 5 of 9 | 1 | ENSP00000396384.2 | |||
LIPH | ENST00000452897.1 | c.112C>A | p.His38Asn | missense_variant | Exon 2 of 2 | 3 | ENSP00000408218.1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152118Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000955 AC: 24AN: 251374Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135848
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1460864Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26AN XY: 726826
GnomAD4 genome AF: 0.0000525 AC: 8AN: 152236Hom.: 0 Cov.: 31 AF XY: 0.0000806 AC XY: 6AN XY: 74434
ClinVar
Submissions by phenotype
Hypotrichosis 7 Pathogenic:3
PM2_Supporting+PM3_VeryStrong+PP1+PP3+PP4 -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.009%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.92 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with LIPH related disorder (ClinVar ID: VCV000030669 /PMID: 19892526). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 19892526). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
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not provided Pathogenic:1
Published functional studies demonstrate a damaging effect on enzyme activity (Shinkuma et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25201209, 25819726, 32667621, 37375751, 36852523, 33988877, 22449147, 35238153, 21537821, 34676598, 22995991, 27774676, 24354445, 19892526, 29346610, 20213768, 24586639) -
Woolly hair, autosomal recessive 2, with or without hypotrichosis Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at