NM_001520.4:c.4096G>A

Variant names:

• chr16-27481179-C-T
• rs1060499746
• NM_001520.4:c.4096G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP5_Moderate BS2

The NM_001520.4(GTF3C1):​c.4096G>A​(p.Glu1366Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: GTF3C1 NM_001520.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.34
• Publications: 2 publications found

Genes affected

GTF3C1 (HGNC:4664): (general transcription factor IIIC subunit 1) Predicted to contribute to DNA binding activity. Predicted to be involved in 5S class rRNA transcription by RNA polymerase III and transcription initiation from RNA polymerase III promoter. Located in nucleolus and 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.

• PP5: Variant 16-27481179-C-T is Pathogenic according to our data. Variant chr16-27481179-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 402157.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001520.4. 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
	GTF3C1	NM_001520.4	MANE Select	c.4096G>A	p.Glu1366Lys	missense	Exon 27 of 37	NP_001511.2	Q12789-2
	GTF3C1	NM_001286242.2		c.4096G>A	p.Glu1366Lys	missense	Exon 27 of 37	NP_001273171.1	Q12789-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTF3C1	ENST00000356183.9	TSL:1 MANE Select	c.4096G>A	p.Glu1366Lys	missense	Exon 27 of 37	ENSP00000348510.4	Q12789-2
	GTF3C1	ENST00000561623.5	TSL:1	c.4096G>A	p.Glu1366Lys	missense	Exon 27 of 37	ENSP00000455417.1	Q12789-3
	GTF3C1	ENST00000917815.1		c.4096G>A	p.Glu1366Lys	missense	Exon 27 of 37	ENSP00000587874.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461804 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111936

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Abnormal brain morphology (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.19
Sift	Benign	0.068	T
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.56
MutPred		0.43		Gain of methylation at E1366 (P = 0.0172)
MVP		0.18
MPC		1.1
ClinPred		0.90	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.57
Mutation Taster		=89/11	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1060499746; hg19: chr16-27492500; COSMIC: COSV62239401; COSMIC: COSV62239401;