8-143726058-G-A
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_198488.5(FAM83H):c.3403C>T(p.Arg1135Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,612,246 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
FAM83H
NM_198488.5 missense
NM_198488.5 missense
Scores
6
5
7
Clinical Significance
Conservation
PhyloP100: 5.25
Genes affected
FAM83H (HGNC:24797): (family with sequence similarity 83 member H) The protein encoded by this gene plays an important role in the structural development and calcification of tooth enamel. Defects in this gene are a cause of amelogenesis imperfecta type 3 (AI3). [provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
High AC in GnomAdExome4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FAM83H | NM_198488.5 | c.3403C>T | p.Arg1135Cys | missense_variant | 5/5 | ENST00000388913.4 | NP_940890.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FAM83H | ENST00000388913.4 | c.3403C>T | p.Arg1135Cys | missense_variant | 5/5 | 5 | NM_198488.5 | ENSP00000373565 | P2 | |
FAM83H | ENST00000650760.1 | c.4006C>T | p.Arg1336Cys | missense_variant | 5/5 | ENSP00000499217 | A2 | |||
FAM83H | ENST00000395103.2 | c.2584C>T | p.Arg862Cys | missense_variant, NMD_transcript_variant | 1/2 | 2 | ENSP00000378535 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.00000819 AC: 2AN: 244314Hom.: 0 AF XY: 0.00000748 AC XY: 1AN XY: 133648
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460046Hom.: 0 Cov.: 83 AF XY: 0.00000551 AC XY: 4AN XY: 726318
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1AN XY: 74332
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 29, 2024 | Variant summary: FAM83H c.3403C>T (p.Arg1135Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 244314 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3403C>T in individuals affected with Amelogenesis Imperfecta, Hypocalcification Type and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Benign
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
P
Vest4
MutPred
Gain of loop (P = 0.0045);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at