rs139422900

Variant names:

• chr9-133043812-G-A
• rs139422900
• NM_012087.4:c.458G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-133043812-G-A
• chr9-133043812-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_012087.4(GTF3C5):​c.458G>A​(p.Arg153Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000298 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: GTF3C5 NM_012087.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.88

Genes affected

GTF3C5 (HGNC:4668): (general transcription factor IIIC subunit 5) 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. Predicted to act upstream of or within skeletal muscle cell differentiation. Located in nucleoplasm. Part of transcription factor TFIIIC complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07683268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTF3C5	NM_012087.4	c.458G>A	p.Arg153Gln	missense_variant	Exon 3 of 11	ENST00000372097.10	NP_036219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTF3C5	ENST00000372097.10	c.458G>A	p.Arg153Gln	missense_variant	Exon 3 of 11	1	NM_012087.4	ENSP00000361169.5

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152156 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000159 AC: 40 AN: 251480 AF XY: 0.000162

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000306 AC: 447 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.000320 AC XY: 233 AN XY: 727228

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000388 AC: 431 AN: 1111962

Other (OTH) AF: 0.000149 AC: 9 AN: 60396

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152156 Hom.: 0 Cov.: 31 AF XY: 0.000229 AC XY: 17 AN XY: 74328

African (AFR) AF: 0.0000724 AC: 3 AN: 41428

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000323 Hom.: 0

Bravo AF: 0.000230

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 23, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.458G>A (p.R153Q) alteration is located in exon 3 (coding exon 3) of the GTF3C5 gene. This alteration results from a G to A substitution at nucleotide position 458, causing the arginine (R) at amino acid position 153 to be replaced by a glutamine (Q). 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	0.071
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;T;.;T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.077	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;.;N;.;.
PhyloP100		1.9
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.34	N;N;N;N;N
REVEL	Benign	0.032
Sift	Benign	0.19	T;T;T;T;T
Sift4G	Benign	0.20	T;D;T;T;T
Polyphen		0.075	B;.;B;.;.
Vest4		0.29
MVP		0.55
MPC		0.43
ClinPred		0.049	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.041
gMVP		0.47
Mutation Taster		=73/27	polymorphism

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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Other links and lift over

dbSNP: rs139422900; hg19: chr9-135919199;