chr9-133042193-G-T

Variant names:

• chr9-133042193-G-T
• rs147553955
• NM_012087.4:c.260G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_012087.4(GTF3C5):​c.260G>T​(p.Arg87Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000521 in 1,613,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R87C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: GTF3C5 NM_012087.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00
• Publications: 1 publications found

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]

GTF3C5 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4079994).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012087.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTF3C5	NM_012087.4	MANE Select	c.260G>T	p.Arg87Leu	missense	Exon 2 of 11	NP_036219.2	Q9Y5Q8-1
	GTF3C5	NM_001122823.2		c.260G>T	p.Arg87Leu	missense	Exon 2 of 12	NP_001116295.1	Q9Y5Q8-3
	GTF3C5	NM_001286709.2		c.51-8590G>T		intron	N/A	NP_001273638.1	H7BY84

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTF3C5	ENST00000372097.10	TSL:1 MANE Select	c.260G>T	p.Arg87Leu	missense	Exon 2 of 11	ENSP00000361169.5	Q9Y5Q8-1
	GTF3C5	ENST00000372108.9	TSL:1	c.260G>T	p.Arg87Leu	missense	Exon 2 of 12	ENSP00000361180.5	Q9Y5Q8-3
	GTF3C5	ENST00000916424.1		c.203G>T	p.Arg68Leu	missense	Exon 2 of 12	ENSP00000586483.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152238 Hom.: 0 Cov.: 32

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: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000115 AC: 29 AN: 251388 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000554 AC: 81 AN: 1461272 Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 49 AN XY: 727012

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000777 AC: 67 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111462

Other (OTH) AF: 0.000232 AC: 14 AN: 60384

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.000123 AC: 15

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.0
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.26
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.016	D
Polyphen		0.99	D
Vest4		0.66
MutPred		0.62		Loss of MoRF binding (P = 0.0412)
MVP		0.80
MPC		1.2
ClinPred		0.47	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.77
gMVP		0.83
Mutation Taster		=81/19	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

Other links and lift over

dbSNP: rs147553955; hg19: chr9-135917580;