rs137854443

Variant names:

• chr8-143727381-C-A
• rs137854443
• NM_198488.5:c.2080G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-143727381-C-A
• chr8-143727381-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_198488.5(FAM83H):​c.2080G>T​(p.Glu694*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000704 in 1,419,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: FAM83H NM_198488.5 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.19
• Publications: 10 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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.412 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-143727381-C-A is Pathogenic according to our data. Variant chr8-143727381-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 778.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198488.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM83H	NM_198488.5	MANE Select	c.2080G>T	p.Glu694*	stop_gained	Exon 5 of 5	NP_940890.4	Q6ZRV2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM83H	ENST00000388913.4	TSL:5 MANE Select	c.2080G>T	p.Glu694*	stop_gained	Exon 5 of 5	ENSP00000373565.3	Q6ZRV2
	FAM83H	ENST00000650760.1		c.2683G>T	p.Glu895*	stop_gained	Exon 5 of 5	ENSP00000499217.1	A0A494C1T9
	FAM83H	ENST00000935286.1		c.2080G>T	p.Glu694*	stop_gained	Exon 5 of 5	ENSP00000605345.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1419874 Hom.: 0 Cov.: 84 AF XY: 0.00000142 AC XY: 1 AN XY: 704522

African (AFR) AF: 0.00 AC: 0 AN: 33066

American (AMR) AF: 0.00 AC: 0 AN: 40450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25572

East Asian (EAS) AF: 0.00 AC: 0 AN: 38382

South Asian (SAS) AF: 0.00 AC: 0 AN: 82896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5592

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1099396

Other (OTH) AF: 0.00 AC: 0 AN: 59178

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Amelogenesis imperfecta, type 3A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.83	D
PhyloP100		5.2
Vest4		0.72
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=19/181	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137854443; hg19: chr8-144809551;