8-143726058-G-A

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

Scores

6
5
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.25
Variant links:
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]

Genome browser will be placed here

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
FAM83HNM_198488.5 linkuse as main transcriptc.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
FAM83HENST00000388913.4 linkuse as main transcriptc.3403C>T p.Arg1135Cys missense_variant 5/55 NM_198488.5 ENSP00000373565 P2
FAM83HENST00000650760.1 linkuse as main transcriptc.4006C>T p.Arg1336Cys missense_variant 5/5 ENSP00000499217 A2
FAM83HENST00000395103.2 linkuse as main transcriptc.2584C>T p.Arg862Cys missense_variant, NMD_transcript_variant 1/22 ENSP00000378535

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152200
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000819
AC:
2
AN:
244314
Hom.:
0
AF XY:
0.00000748
AC XY:
1
AN XY:
133648
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000584
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1460046
Hom.:
0
Cov.:
83
AF XY:
0.00000551
AC XY:
4
AN XY:
726318
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000448
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152200
Hom.:
0
Cov.:
34
AF XY:
0.0000135
AC XY:
1
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 29, 2024Variant 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.28
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.18
T
Eigen
Uncertain
0.19
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.92
D
M_CAP
Uncertain
0.10
D
MetaRNN
Uncertain
0.54
D
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.0
L
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.96
D
PROVEAN
Pathogenic
-5.7
D
REVEL
Benign
0.22
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
0.82
P
Vest4
0.72
MutPred
0.44
Gain of loop (P = 0.0045);
MVP
0.093
MPC
1.3
ClinPred
0.99
D
GERP RS
4.1
Varity_R
0.085
gMVP
0.63

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1272345829; hg19: chr8-144808228; API