chr19-6380574-C-T

Variant names:

• chr19-6380574-C-T
• rs756438444
• NM_002096.3:c.1348G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002096.3(GTF2F1):​c.1348G>A​(p.Gly450Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G450G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: GTF2F1 NM_002096.3 missense, splice_region
• Scores: Splicing: ADA: 0.00003023
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17
• Publications: 0 publications found

Genes affected

GTF2F1 (HGNC:4652): (general transcription factor IIF subunit 1) Enables several functions, including RNA polymerase II general transcription initiation factor activity; phosphatase activator activity; and promoter-specific chromatin binding activity. Involved in several processes, including positive regulation of transcription by RNA polymerase II; response to virus; and transcription initiation from RNA polymerase II promoter. Located in cell junction and nucleoplasm. Part of transcription factor TFIID complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.055540383).
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002096.3. 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
	GTF2F1	NM_002096.3	MANE Select	c.1348G>A	p.Gly450Ser	missense splice_region	Exon 12 of 13	NP_002087.2	P35269

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTF2F1	ENST00000394456.10	TSL:1 MANE Select	c.1348G>A	p.Gly450Ser	missense splice_region	Exon 12 of 13	ENSP00000377969.3	P35269
	GTF2F1	ENST00000869875.1		c.1345G>A	p.Gly449Ser	missense splice_region	Exon 12 of 13	ENSP00000539934.1
	GTF2F1	ENST00000933129.1		c.1342G>A	p.Gly448Ser	missense splice_region	Exon 12 of 13	ENSP00000603188.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251418 AF XY: 0.00000736

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: 0.0000926

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461636 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727122

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53374

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

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111820

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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	0.072
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.056
Sift	Benign	0.63	T
Sift4G	Benign	0.97	T
Polyphen		0.0050	B
Vest4		0.16
MutPred		0.33		Gain of glycosylation at G450 (P = 0.036)
MVP		0.28
MPC		0.25
ClinPred		0.063	T
GERP RS		2.1
Varity_R		0.062
gMVP		0.47
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.022
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: rs756438444; hg19: chr19-6380585; COSMIC: COSV55532774; COSMIC: COSV55532774;