9-132670645-C-T

Variant names:

• chr9-132670645-C-T
• rs756998341
• NM_012204.4:c.47C>T

Variant summary

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

The NM_012204.4(GTF3C4):​c.47C>T​(p.Pro16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000378 in 1,321,834 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: GTF3C4 NM_012204.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.858
• Publications: 0 publications found

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]

DDX31 (HGNC:16715): (DEAD-box helicase 31) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this DEAD box protein family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a member of this family. The function of this member has not been determined. Alternative splicing of this gene generates multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2016]

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=0.20946106).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012204.4. 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
	GTF3C4	NM_012204.4	MANE Select	c.47C>T	p.Pro16Leu	missense	Exon 1 of 5	NP_036336.2	Q9UKN8
	GTF3C4	NR_133925.1		n.611C>T		non_coding_transcript_exon	Exon 1 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTF3C4	ENST00000372146.5	TSL:1 MANE Select	c.47C>T	p.Pro16Leu	missense	Exon 1 of 5	ENSP00000361219.4	Q9UKN8
	GTF3C4	ENST00000898845.1		c.47C>T	p.Pro16Leu	missense	Exon 1 of 5	ENSP00000568904.1
	GTF3C4	ENST00000483873.6	TSL:3	c.47C>T	p.Pro16Leu	missense	Exon 1 of 3	ENSP00000431378.1	F2Z356

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000378 AC: 5 AN: 1321834 Hom.: 0 Cov.: 32 AF XY: 0.00000463 AC XY: 3 AN XY: 647994

African (AFR) AF: 0.00 AC: 0 AN: 27682

American (AMR) AF: 0.00 AC: 0 AN: 23660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19950

East Asian (EAS) AF: 0.00 AC: 0 AN: 34502

South Asian (SAS) AF: 0.00 AC: 0 AN: 67316

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3896

European-Non Finnish (NFE) AF: 0.00000379 AC: 4 AN: 1055470

Other (OTH) AF: 0.0000182 AC: 1 AN: 54916

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.086
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.86
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.11
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.15
MutPred		0.11		Loss of relative solvent accessibility (P = 0.0676)
MVP		0.72
MPC		0.74
ClinPred		0.29	T
GERP RS		3.3
PromoterAI		-0.16	Neutral
Varity_R		0.089
gMVP		0.34
Mutation Taster		=96/4	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: rs756998341; hg19: chr9-135546032;