rs1137806

chr8-143727968-G-Achr8-143727968-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198488.5(FAM83H):c.1493C>T(p.Pro498Leu) variant causes a missense change. The variant allele was found at a frequency of 0.136 in 1,568,440 control chromosomes in the GnomAD database, including 16,624 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1362 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15262 hom.)
• Consequence: FAM83H NM_198488.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052135885).
• BP6: Variant 8-143727968-G-A is Benign according to our data. Variant chr8-143727968-G-A is described in ClinVar as [Benign]. Clinvar id is 263132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143727968-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM83H	NM_198488.5	c.1493C>T	p.Pro498Leu	missense_variant	5/5	ENST00000388913.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM83H	ENST00000388913.4	c.1493C>T	p.Pro498Leu	missense_variant	5/5	5	NM_198488.5	P2
FAM83H	ENST00000650760.1	c.2096C>T	p.Pro699Leu	missense_variant	5/5			A2
FAM83H	ENST00000395103.2	c.674C>T	p.Pro225Leu	missense_variant, NMD_transcript_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17125 AN: 151832 Hom.: 1360 Cov.: 33

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.102

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.136

GnomAD3 exomes AF: 0.165 AC: 28947 AN: 175774 Hom.: 2789 AF XY: 0.170 AC XY: 16539 AN XY: 97492

Gnomad AFR exome AF: 0.0214

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.249

Gnomad SAS exome AF: 0.282

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.138 AC: 196110 AN: 1416496 Hom.: 15262 Cov.: 39 AF XY: 0.142 AC XY: 99957 AN XY: 702418

Gnomad4 AFR exome AF: 0.0207

Gnomad4 AMR exome AF: 0.176

Gnomad4 ASJ exome AF: 0.148

Gnomad4 EAS exome AF: 0.253

Gnomad4 SAS exome AF: 0.272

Gnomad4 FIN exome AF: 0.168

Gnomad4 NFE exome AF: 0.125

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.113 AC: 17118 AN: 151944 Hom.: 1362 Cov.: 33 AF XY: 0.119 AC XY: 8835 AN XY: 74288

Gnomad4 AFR AF: 0.0253

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.249

Gnomad4 SAS AF: 0.293

Gnomad4 FIN AF: 0.166

Gnomad4 NFE AF: 0.124

Gnomad4 OTH AF: 0.136

Alfa AF: 0.0891 Hom.: 157

Bravo AF: 0.106

TwinsUK AF: 0.125 AC: 463

ALSPAC AF: 0.122 AC: 470

ESP6500AA AF: 0.0203 AC: 64

ESP6500EA AF: 0.108 AC: 767

ExAC AF: 0.137 AC: 15023

Asia WGS AF: 0.272 AC: 942 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Amelogenesis imperfecta, hypocalcification type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.66	D
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	P
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.16
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.057	T
Polyphen		1.0	D
Vest4		0.10
MPC		0.77
ClinPred		0.021	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.11
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; COSMIC: COSV66353640;