NM_012087.4:c.20A>G

Variant names:

• chr9-133031031-A-G
• NM_012087.4:c.20A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012087.4(GTF3C5):​c.20A>G​(p.Asp7Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D7E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GTF3C5 NM_012087.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.136
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.079786986).

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.20A>G	p.Asp7Gly	missense	Exon 1 of 11	NP_036219.2	Q9Y5Q8-1
	GTF3C5	NM_001122823.2		c.20A>G	p.Asp7Gly	missense	Exon 1 of 12	NP_001116295.1	Q9Y5Q8-3
	GTF3C5	NM_001286709.2		c.-84A>G		5_prime_UTR	Exon 1 of 9	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.20A>G	p.Asp7Gly	missense	Exon 1 of 11	ENSP00000361169.5	Q9Y5Q8-1
	GTF3C5	ENST00000372108.9	TSL:1	c.20A>G	p.Asp7Gly	missense	Exon 1 of 12	ENSP00000361180.5	Q9Y5Q8-3
	GTF3C5	ENST00000916424.1		c.20A>G	p.Asp7Gly	missense	Exon 1 of 12	ENSP00000586483.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	0.071
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	10
DANN	Benign	0.76
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.89	L
PhyloP100		0.14
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.017
Sift	Benign	0.32	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.061
MutPred		0.22		Loss of helix (P = 0.0376)
MVP		0.32
MPC		0.49
ClinPred		0.15	T
GERP RS		2.5
PromoterAI		-0.0074	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.12
gMVP		0.64
Mutation Taster		=95/5	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

hg19: chr9-135906418;