Genetic Variant FAM53C:p.His77Tyr (chr5-138344917-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016605.3(FAM53C):c.229C>T(p.His77Tyr) 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 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FAM53C
NM_016605.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.46

Variant links:

Genes affected

FAM53C (HGNC:1336): (family with sequence similarity 53 member C) The protein encoded by this gene belongs to the FAM53 protein family. FAM53 protein family members bind to a transcriptional regulator that modulates cell proliferation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2017]

FAM53C links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17535022).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM53C	NM_016605.3 link	c.229C>T	p.His77Tyr	missense_variant	Exon 4 of 5	ENST00000239906.10	NP_057689.1	Q9NYF3
FAM53C	NM_001135647.2 link	c.229C>T	p.His77Tyr	missense_variant	Exon 4 of 5		NP_001129119.1	Q9NYF3
FAM53C	NM_001350195.2 link	c.199C>T	p.His67Tyr	missense_variant	Exon 4 of 5		NP_001337124.1
FAM53C	NM_001350194.2 link	c.137-541C>T		intron_variant	Intron 3 of 4		NP_001337123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM53C	ENST00000239906.10 link	c.229C>T	p.His77Tyr	missense_variant	Exon 4 of 5	1	NM_016605.3	ENSP00000239906.5		Q9NYF3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251290

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS 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:

1461746

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.229C>T (p.H77Y) alteration is located in exon 4 (coding exon 3) of the FAM53C gene. This alteration results from a C to T substitution at nucleotide position 229, causing the histidine (H) at amino acid position 77 to be replaced by a tyrosine (Y). 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

0.089

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.065

T;T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

.;T;T

M_CAP

Benign

0.0052

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.8

L;L;.

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.31

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.81

T;T;D

Sift4G

Benign

0.18

T;T;T

Polyphen

0.94

P;P;.

Vest4

0.52

MutPred

0.14

Gain of phosphorylation at H77 (P = 0.0454);Gain of phosphorylation at H77 (P = 0.0454);.;

MVP

0.11

MPC

0.51

ClinPred

0.46

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.097

gMVP

0.21

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