8-143727968-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_198488.5(FAM83H):c.1493C>G(p.Pro498Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000319 in 1,568,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P498L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: FAM83H NM_198488.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.89

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34910163).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM83H	NM_198488.5	c.1493C>G	p.Pro498Arg	missense_variant	5/5	ENST00000388913.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM83H	ENST00000388913.4	c.1493C>G	p.Pro498Arg	missense_variant	5/5	5	NM_198488.5	P2
FAM83H	ENST00000650760.1	c.2096C>G	p.Pro699Arg	missense_variant	5/5			A2
FAM83H	ENST00000395103.2	c.674C>G	p.Pro225Arg	missense_variant, NMD_transcript_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151850 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1416654 Hom.: 0 Cov.: 39 AF XY: 0.00000142 AC XY: 1 AN XY: 702502

Gnomad4 AFR exome AF: 0.0000910

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151850 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74174

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.68	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.25
MutPred		0.36		Gain of solvent accessibility (P = 0.0171);
MVP		0.043
MPC		1.1
ClinPred		0.96	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.088
gMVP		0.45

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

Other links and lift over

dbSNP: rs1137806; hg19: chr8-144810138;