Genetic Variant NM_012204.4:c.481A>G (chr9-132678100-A-G) – 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_012204.4(GTF3C4):c.481A>G(p.Met161Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000638 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

GTF3C4
NM_012204.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.369

Variant links:

Genes affected

GTF3C4 (HGNC:4667): (general transcription factor IIIC subunit 4) Predicted to enable enzyme activator activity. Predicted to contribute to DNA binding activity. Predicted to be involved in 5S class rRNA transcription by RNA polymerase III and tRNA transcription by RNA polymerase III. Located in mitochondrion and nucleoplasm. Part of transcription factor TFIIIC complex. [provided by Alliance of Genome Resources, Apr 2022]

GTF3C4 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=0.05678761).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTF3C4	NM_012204.4 link	c.481A>G	p.Met161Val	missense_variant	Exon 2 of 5	ENST00000372146.5	NP_036336.2	Q9UKN8B3KNH2
GTF3C4	NR_133925.1 link	n.1045A>G		non_coding_transcript_exon_variant	Exon 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTF3C4	ENST00000372146.5 link	c.481A>G	p.Met161Val	missense_variant	Exon 2 of 5	1	NM_012204.4	ENSP00000361219.4		Q9UKN8
GTF3C4	ENST00000483873.6 link	c.420+61A>G		intron_variant	Intron 2 of 2	3		ENSP00000431378.1		F2Z356

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152246

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251426

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000670

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.0000728

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74386

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:

0.0000941

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000529

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.00

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

Jul 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.481A>G (p.M161V) alteration is located in exon 2 (coding exon 2) of the GTF3C4 gene. This alteration results from a A to G substitution at nucleotide position 481, causing the methionine (M) at amino acid position 161 to be replaced by a valine (V). 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

0.085

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.0040

DANN

Benign

0.37

DEOGEN2

Benign

0.093

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.83

M_CAP

Benign

0.0094

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.52

REVEL

Benign

0.037

Sift

Benign

0.46

Sift4G

Benign

0.21

Polyphen

0.0010

Vest4

0.30

MVP

0.19

MPC

0.75

ClinPred

0.018

GERP RS

-10

Varity_R

0.028

gMVP

0.35

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