8-143726063-T-C

Position:

• chr8-143726063-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198488.5(FAM83H):​c.3398A>G​(p.Tyr1133Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: FAM83H NM_198488.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM83H	NM_198488.5	c.3398A>G	p.Tyr1133Cys	missense_variant	5/5	ENST00000388913.4	NP_940890.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM83H	ENST00000388913.4	c.3398A>G	p.Tyr1133Cys	missense_variant	5/5	5	NM_198488.5	ENSP00000373565	P2
FAM83H	ENST00000650760.1	c.4001A>G	p.Tyr1334Cys	missense_variant	5/5			ENSP00000499217	A2
FAM83H	ENST00000395103.2	c.2579A>G	p.Tyr860Cys	missense_variant, NMD_transcript_variant	1/2	2		ENSP00000378535

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000411 AC: 1 AN: 243470 Hom.: 0 AF XY: 0.00000750 AC XY: 1 AN XY: 133352

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000914

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 82

GnomAD4 genome Cov.: 34

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2022

The c.3398A>G (p.Y1133C) alteration is located in exon 5 (coding exon 4) of the FAM83H gene. This alteration results from a A to G substitution at nucleotide position 3398, causing the tyrosine (Y) at amino acid position 1133 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.086
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.91	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.65	P
Vest4		0.79
MVP		0.20
MPC		1.2
ClinPred		0.98	D
GERP RS		2.5
Varity_R		0.12
gMVP		0.65

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: rs370499410; hg19: chr8-144808233;