16-27481179-C-T

Position:

• chr16-27481179-C-T

Variant summary

Our verdict is Likely benign. Variant got -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

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

Verdict is Likely_benign. Variant got -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 id is 402157.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-27481179-C-T is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GTF3C1	NM_001520.4	c.4096G>A	p.Glu1366Lys	missense_variant	27/37	ENST00000356183.9	NP_001511.2
GTF3C1	NM_001286242.2	c.4096G>A	p.Glu1366Lys	missense_variant	27/37		NP_001273171.1
GTF3C1	XM_017023188.3	c.3907G>A	p.Glu1303Lys	missense_variant	26/36		XP_016878677.1
GTF3C1	XM_047434036.1	c.3907G>A	p.Glu1303Lys	missense_variant	26/36		XP_047289992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GTF3C1	ENST00000356183.9	c.4096G>A	p.Glu1366Lys	missense_variant	27/37	1	NM_001520.4	ENSP00000348510	P2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

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Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.90	N;N
REVEL	Benign	0.19
Sift	Benign	0.068	T;T
Sift4G	Benign	0.10	T;T
Polyphen		1.0	D;D
Vest4		0.56
MutPred		0.43		Gain of methylation at E1366 (P = 0.0172);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060499746; hg19: chr16-27492500; COSMIC: COSV62239401; COSMIC: COSV62239401;