Variant 8-143726375-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_198488.5(FAM83H):c.3086A>C(p.Asn1029Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000844 in 1,610,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

FAM83H
NM_198488.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.62

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01567927).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000486 (74/152308) while in subpopulation AFR AF= 0.0014 (58/41558). AF 95% confidence interval is 0.00111. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 74 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM83H	NM_198488.5 linkuse as main transcript	c.3086A>C	p.Asn1029Thr	missense_variant	5/5	ENST00000388913.4	NP_940890.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
FAM83H	ENST00000388913.4 linkuse as main transcript	c.3086A>C	p.Asn1029Thr	missense_variant	5/5	5	NM_198488.5	ENSP00000373565	P2
FAM83H	ENST00000650760.1 linkuse as main transcript	c.3689A>C	p.Asn1230Thr	missense_variant	5/5			ENSP00000499217	A2
FAM83H	ENST00000395103.2 linkuse as main transcript	c.2267A>C	p.Asn756Thr	missense_variant, NMD_transcript_variant	1/2	2		ENSP00000378535

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000115

AC:

AN:

235504

Hom.:

AF XY:

0.0000851

AC XY:

AN XY:

129226

show subpopulations

Gnomad AFR exome

AF:

0.00182

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:

0.00000961

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000425

AC:

AN:

1458588

Hom.:

Cov.:

AF XY:

0.0000400

AC XY:

AN XY:

725474

show subpopulations

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000486

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.000914

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000127

Hom.:

Bravo

AF:

0.000657

ESP6500AA

AF:

0.00259

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000207

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2022

The c.3086A>C (p.N1029T) alteration is located in exon 5 (coding exon 4) of the FAM83H gene. This alteration results from a A to C substitution at nucleotide position 3086, causing the asparagine (N) at amino acid position 1029 to be replaced by a threonine (T). 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

Benign

0.28

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.022

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.87

M_CAP

Benign

0.039

MetaRNN

Benign

0.016

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

0.61

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.19

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.023

Polyphen

0.99

Vest4

0.49

MVP

0.15

MPC

1.1

ClinPred

0.18

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over