rs189033490

Variant names:

• chr8-143729170-G-A
• rs189033490
• NM_198488.5:c.601C>T

Variant summary

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

The ENST00000388913.4(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 ENST00000388913.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.98
• Publications: 12 publications found

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]

FAM83H Gene-Disease associations (from GenCC):

• amelogenesis imperfecta, type 3A

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -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 VariationId is 402847.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 273 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000388913.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM83H	NM_198488.5	MANE Select	c.601C>T	p.Gln201*	stop_gained	Exon 3 of 5	NP_940890.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM83H	ENST00000388913.4	TSL:5 MANE Select	c.601C>T	p.Gln201*	stop_gained	Exon 3 of 5	ENSP00000373565.3
	FAM83H	ENST00000650760.1		c.1204C>T	p.Gln402*	stop_gained	Exon 3 of 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

GnomAD2 exomes AF: 0.00168 AC: 418 AN: 249456 AF XY: 0.00171

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 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

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.000559 AC: 25 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000804 AC: 21 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000452 AC: 39 AN: 86258

European-Finnish (FIN) AF: 0.00125 AC: 66 AN: 52992

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00298 AC: 3314 AN: 1111992

Other (OTH) AF: 0.00189 AC: 114 AN: 60392

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

African (AFR) AF: 0.000457 AC: 19 AN: 41560

American (AMR) AF: 0.00118 AC: 18 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00300 AC: 204 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00224 Hom.: 2

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Amelogenesis imperfecta, type 3A (2)
-	-	1	FAM83H-related disorder (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.0
Vest4		0.78
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=30/170	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs189033490; hg19: chr8-144811340;