Genetic Variant FAM53A:p.Arg365Cys (chr4-1641397-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001174070.3(FAM53A):c.1093C>T(p.Arg365Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000466 in 1,611,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R365H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

FAM53A
NM_001174070.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.652

Publications

1 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019063562).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001174070.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM53A	NM_001174070.3	MANE Select	c.1093C>T	p.Arg365Cys	missense	Exon 5 of 5	NP_001167541.1	Q6NSI3
FAM53A	NM_001013622.3		c.1093C>T	p.Arg365Cys	missense	Exon 5 of 5	NP_001013644.1	Q6NSI3
FAM53A	NM_001297435.1		c.*164C>T		3_prime_UTR	Exon 6 of 6	NP_001284364.1	C9JYQ7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM53A	ENST00000308132.11	TSL:2 MANE Select	c.1093C>T	p.Arg365Cys	missense	Exon 5 of 5	ENSP00000310057.6	Q6NSI3
FAM53A	ENST00000472884.6	TSL:1	c.1093C>T	p.Arg365Cys	missense	Exon 5 of 5	ENSP00000426260.1	Q6NSI3
FAM53A	ENST00000461064.5	TSL:2	c.1093C>T	p.Arg365Cys	missense	Exon 4 of 4	ENSP00000418243.1	Q6NSI3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

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:

0.000387

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000646

AC:

AN:

247556

AF XY:

0.0000820

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000300

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000165

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000494

AC:

AN:

1458776

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

725828

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33262

American (AMR)

AF:

0.0000230

AC:

AN:

43504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25954

East Asian (EAS)

AF:

0.000101

AC:

AN:

39688

South Asian (SAS)

AF:

0.000477

AC:

AN:

85972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1111076

Other (OTH)

AF:

0.0000498

AC:

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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

AF:

0.0000197

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41576

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000388

AC:

AN:

5156

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000824

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.66

CADD

Benign

7.2

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.00036

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0072

LIST_S2

Benign

0.41

M_CAP

Benign

0.0063

MetaRNN

Benign

0.019

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

PhyloP100

-0.65

PrimateAI

Benign

0.43

PROVEAN

Benign

1.0

REVEL

Benign

0.029

Sift

Benign

0.16

Sift4G

Benign

0.093

Polyphen

0.0

Vest4

0.056

MVP

0.14

MPC

0.12

ClinPred

0.018

GERP RS

-4.8

Varity_R

0.032

gMVP

0.050

Mutation Taster

=98/2

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over