Genetic Variant FAM47A:p.Val785Ile (chrX-34129926-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_203408.4(FAM47A):c.2353G>A(p.Val785Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,195,757 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000061 ( 0 hom. 19 hem. )

Consequence

FAM47A
NM_203408.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:2

Conservation

PhyloP100: -0.269

Variant links:

Genes affected

FAM47A (HGNC:29962): (family with sequence similarity 47 member A)

FAM47A links:

ENSG00000233928 (HGNC:):

ENSG00000233928 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06980491).

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM47A	NM_203408.4 link	c.2353G>A	p.Val785Ile	missense_variant	Exon 1 of 1	ENST00000346193.5	NP_981953.2	Q5JRC9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM47A	ENST00000346193.5 link	c.2353G>A	p.Val785Ile	missense_variant	Exon 1 of 1	6	NM_203408.4	ENSP00000345029.3		Q5JRC9

Frequencies

GnomAD3 genomes

AF:

0.0000981

AC:

AN:

112124

Hom.:

Cov.:

AF XY:

0.0000875

AC XY:

AN XY:

34276

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000531

AC:

AN:

169342

Hom.:

AF XY:

0.0000353

AC XY:

AN XY:

56634

show subpopulations

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:

0.0000642

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000104

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000609

AC:

AN:

1083633

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

352655

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000194

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000767

Gnomad4 OTH exome

AF:

0.0000220

GnomAD4 genome

AF:

0.0000981

AC:

AN:

112124

Hom.:

Cov.:

AF XY:

0.0000875

AC XY:

AN XY:

34276

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2353G>A (p.V785I) alteration is located in exon 1 (coding exon 1) of the FAM47A gene. This alteration results from a G to A substitution at nucleotide position 2353, causing the valine (V) at amino acid position 785 to be replaced by an isoleucine (I). 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

0.11

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-1.0

CADD

Benign

3.8

DANN

Benign

0.65

DEOGEN2

Benign

0.010

T;.

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.33

T;T

M_CAP

Benign

0.00071

MetaRNN

Benign

0.070

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

N;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.69

N;.

REVEL

Benign

0.020

Sift

Benign

0.085

T;.

Sift4G

Uncertain

0.038

D;D

Polyphen

0.083

B;.

Vest4

0.061

MutPred

0.16

Loss of catalytic residue at V785 (P = 0.0302);.;

MVP

0.043

MPC

0.16

ClinPred

0.015

GERP RS

0.099

Varity_R

0.045

gMVP

0.061

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