chr1-17262194-T-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PP5_Very_StrongBP4BS1_Supporting
The NM_016233.2(PADI3):c.335T>A(p.Leu112His) variant causes a missense change. The variant allele was found at a frequency of 0.00699 in 1,608,134 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_016233.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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PADI3 | NM_016233.2 | c.335T>A | p.Leu112His | missense_variant | Exon 3 of 16 | ENST00000375460.3 | NP_057317.2 | |
PADI3 | XM_011541571.3 | c.221T>A | p.Leu74His | missense_variant | Exon 3 of 16 | XP_011539873.1 | ||
PADI3 | XM_011541572.3 | c.335T>A | p.Leu112His | missense_variant | Exon 3 of 12 | XP_011539874.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00489 AC: 744AN: 152110Hom.: 3 Cov.: 32
GnomAD3 exomes AF: 0.00455 AC: 1108AN: 243658Hom.: 2 AF XY: 0.00439 AC XY: 580AN XY: 132024
GnomAD4 exome AF: 0.00721 AC: 10500AN: 1455906Hom.: 38 Cov.: 30 AF XY: 0.00689 AC XY: 4993AN XY: 724364
GnomAD4 genome AF: 0.00489 AC: 745AN: 152228Hom.: 3 Cov.: 32 AF XY: 0.00449 AC XY: 334AN XY: 74440
ClinVar
Submissions by phenotype
Uncombable hair syndrome 1 Pathogenic:6
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PS3, PM3_Strong, PP3 -
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NM_016233.2:c.335T>A in the PADI3 gene has an allele frequency of 0.007 in European(non-Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that c.335T>A has affected transglutaminase activity of TGM3 produced in HEK293T cells (PMID: 27866708). It was detected in multiple individuals with autosomal recessive Uncombable hair syndrome, homozygous c.335T>A, compound heterozygous with c.1813C>A, and c.881C>T, respectively (PMID: 27866708). The patient's phenotype is highly specific for PADI3 gene(PMID:27866708). Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MutationAssessor. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PS3; PM3_Strong; PP4; PP3. -
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not provided Pathogenic:6
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Published functional studies demonstrate a damaging effect; specifically, the L112H variant is associated with absent enzyme activity and abnormal enzyme aggregation (PMID: 27866708); 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: 31952341, 27866708, 34426522, 34297361, 35751533, 36044230, 36541401, 36920900) -
PADI3: PM3:Very Strong, PM2:Supporting -
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PADI3-related disorder Pathogenic:1
The PADI3 c.335T>A variant is predicted to result in the amino acid substitution p.Leu112His. This variant has been reported in the homozygous and compound heterozygous states with another variant [c.881C>T (p.Ala294Val)] to be causative for autosomal recessive uncombable hair syndrome in several unrelated patients (Basmanav et al. 2016. PubMed ID: 27866708; OMIM #191480). This variant is reported in 0.70% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, we classify this variant as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at