rs189033490

Positions:

• chr8-143729170-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 8P and 9B. PVS1 BP6 BS1 BS2

The NM_198488.5(FAM83H):​c.601C>T​(p.Gln201*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,613,740 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (6 hom.)
• Consequence: FAM83H NM_198488.5 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.98

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 Likely_benign. Variant got -1 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 8-143729170-G-A is Benign according to our data. Variant chr8-143729170-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 402847.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00179 (273/152310) while in subpopulation NFE AF= 0.003 (204/68028). AF 95% confidence interval is 0.00266. There are 1 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 273 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM83H	NM_198488.5	c.601C>T	p.Gln201*	stop_gained	3/5	ENST00000388913.4	NP_940890.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM83H	ENST00000388913.4	c.601C>T	p.Gln201*	stop_gained	3/5	5	NM_198488.5	ENSP00000373565.3
FAM83H	ENST00000650760.1	c.1204C>T	p.Gln402*	stop_gained	3/5			ENSP00000499217.1

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 273 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00300

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00168 AC: 418 AN: 249456 Hom.: 0 AF XY: 0.00171 AC XY: 231 AN XY: 135396

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00294

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00247 AC: 3603 AN: 1461430 Hom.: 6 Cov.: 37 AF XY: 0.00245 AC XY: 1784 AN XY: 727042

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000452

Gnomad4 FIN exome AF: 0.00125

Gnomad4 NFE exome AF: 0.00298

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00179 AC: 273 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.00175 AC XY: 130 AN XY: 74478

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00300

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00212 Hom.: 1

Bravo AF: 0.00168

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000723 AC: 3

ESP6500EA AF: 0.00191 AC: 16

ExAC AF: 0.00178 AC: 215

EpiCase AF: 0.00185

EpiControl AF: 0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: LOF disease mechanism for Amelogenesis imperfecta, hypocalcified. This variant has been associated with a different phenotype, intraocular pressure. -

FAM83H-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.77	D
Vest4		0.78
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs189033490; hg19: chr8-144811340;