Genetic Variant FAM83E:p.Pro432Thr (chr19-48601252-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017708.4(FAM83E):c.1294C>A(p.Pro432Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,602,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00094 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 0 hom. )

Consequence

FAM83E
NM_017708.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.586

Variant links:

Genes affected

FAM83E (HGNC:25972): (family with sequence similarity 83 member E) Enables protein kinase binding activity. Predicted to be involved in signal transduction. [provided by Alliance of Genome Resources, Apr 2022]

FAM83E links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009040803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM83E	NM_017708.4 link	c.1294C>A	p.Pro432Thr	missense_variant	Exon 7 of 7	ENST00000263266.4	NP_060178.2	Q2M2I3
FAM83E	XM_024451561.2 link	c.1294C>A	p.Pro432Thr	missense_variant	Exon 7 of 7		XP_024307329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM83E	ENST00000263266.4 link	c.1294C>A	p.Pro432Thr	missense_variant	Exon 7 of 7	1	NM_017708.4	ENSP00000263266.2		Q2M2I3

Frequencies

GnomAD3 genomes

AF:

0.000940

AC:

143

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00165

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000640

AC:

143

AN:

223566

Hom.:

AF XY:

0.000663

AC XY:

AN XY:

122256

show subpopulations

Gnomad AFR exome

AF:

0.000388

Gnomad AMR exome

AF:

0.000375

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000103

Gnomad NFE exome

AF:

0.00124

Gnomad OTH exome

AF:

0.000182

GnomAD4 exome

AF:

0.00142

AC:

2057

AN:

1449868

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

1000

AN XY:

720088

show subpopulations

Gnomad4 AFR exome

AF:

0.000361

Gnomad4 AMR exome

AF:

0.000302

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000134

Gnomad4 NFE exome

AF:

0.00174

Gnomad4 OTH exome

AF:

0.00161

GnomAD4 genome

AF:

0.000939

AC:

143

AN:

152290

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00165

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000806

Hom.:

Bravo

AF:

0.00108

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000274

AC:

ESP6500EA

AF:

0.00185

AC:

ExAC

AF:

0.000524

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1294C>A (p.P432T) alteration is located in exon 5 (coding exon 5) of the FAM83E gene. This alteration results from a C to A substitution at nucleotide position 1294, causing the proline (P) at amino acid position 432 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

0.087

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.57

M_CAP

Benign

0.010

MetaRNN

Benign

0.0090

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.97

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.1

REVEL

Benign

0.033

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.090

Vest4

0.096

MVP

0.072

MPC

0.30

ClinPred

0.041

GERP RS

1.4

Varity_R

0.12

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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