Genetic Variant FAM83H:p.Ser1098Asn (chr8-143726168-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_198488.5(FAM83H):c.3293G>A(p.Ser1098Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1098I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FAM83H
NM_198488.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.20

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

amelogenesis imperfecta, type 3A
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

FAM83H links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06786162).

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.3293G>A	p.Ser1098Asn	missense	Exon 5 of 5	NP_940890.4	Q6ZRV2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM83H	ENST00000388913.4	TSL:5 MANE Select	c.3293G>A	p.Ser1098Asn	missense	Exon 5 of 5	ENSP00000373565.3	Q6ZRV2
FAM83H	ENST00000650760.1		c.3896G>A	p.Ser1299Asn	missense	Exon 5 of 5	ENSP00000499217.1	A0A494C1T9
FAM83H	ENST00000935286.1		c.3293G>A	p.Ser1098Asn	missense	Exon 5 of 5	ENSP00000605345.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000418

AC:

AN:

239234

AF XY:

0.00000763

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459756

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726172

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.0000448

AC:

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111606

Other (OTH)

AF:

0.00

AC:

AN:

60320

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000829

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0074

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.038

FATHMM_MKL

Uncertain

0.91

M_CAP

Benign

0.0087

MetaRNN

Benign

0.068

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

3.2

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.3

REVEL

Benign

0.030

Sift

Benign

0.081

Sift4G

Uncertain

0.059

Polyphen

0.015

Vest4

0.068

MutPred

0.21

Loss of phosphorylation at S1098 (P = 0.0157)

MVP

0.068

MPC

0.31

ClinPred

0.32

GERP RS

4.1

Varity_R

0.14

gMVP

0.38

Mutation Taster

=92/8

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over