rs796065022

Variant names:

• chr8-143727587-AGG-A
• rs796065022
• NM_198488.5:c.1872_1873delCC

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.1872_1873delCC​(p.Leu625AlafsTer79) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: FAM83H NM_198488.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.42
• Publications: 5 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_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. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-143727587-AGG-A is Pathogenic according to our data. Variant chr8-143727587-AGG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 779.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM83H	NM_198488.5	MANE Select	c.1872_1873delCC	p.Leu625AlafsTer79	frameshift	Exon 5 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.1872_1873delCC	p.Leu625AlafsTer79	frameshift	Exon 5 of 5	ENSP00000373565.3
	FAM83H	ENST00000650760.1		c.2475_2476delCC	p.Leu826AlafsTer79	frameshift	Exon 5 of 5	ENSP00000499217.1
	FAM83H	ENST00000395103.2	TSL:2	n.1050_1051delCC		non_coding_transcript_exon	Exon 1 of 2	ENSP00000378535.2

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

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
PhyloP100		2.4
Mutation Taster		=12/188	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: rs796065022; hg19: chr8-144809757;