Genetic Variant FAM53A:p.Asp391Asn (chr4-1641319-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001174070.3(FAM53A):c.1171G>A(p.Asp391Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000822 in 1,460,108 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

FAM53A
NM_001174070.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.98

Variant links:

Genes affected

FAM53A (HGNC:31860): (family with sequence similarity 53 member A) Predicted to be involved in protein import into nucleus. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

FAM53A links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
FAM53A	NM_001174070.3 link	c.1171G>A	p.Asp391Asn	missense_variant	Exon 5 of 5	ENST00000308132.11	NP_001167541.1	Q6NSI3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM53A	ENST00000308132.11 link	c.1171G>A	p.Asp391Asn	missense_variant	Exon 5 of 5	2	NM_001174070.3	ENSP00000310057.6		Q6NSI3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000242

AC:

AN:

248180

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134636

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000117

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:

0.00000892

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1460108

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726432

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.000113

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1171G>A (p.D391N) alteration is located in exon 5 (coding exon 4) of the FAM53A gene. This alteration results from a G to A substitution at nucleotide position 1171, causing the aspartic acid (D) at amino acid position 391 to be replaced by an asparagine (N). 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

Uncertain

0.41

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

T;T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

D;.;.

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Benign

-0.33

MutationAssessor

Benign

1.8

L;L;L

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Benign

0.23

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.78

MutPred

0.39

Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);

MVP

0.68

MPC

0.44

ClinPred

0.94

GERP RS

3.8

Varity_R

0.76

gMVP

0.22

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