19-6380930-C-T

Variant names:

• chr19-6380930-C-T
• rs370397042
• NM_002096.3:c.1205G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002096.3(GTF2F1):​c.1205G>A​(p.Arg402Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000431 in 1,576,204 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. R402W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: GTF2F1 NM_002096.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050388306).
• BS2: High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTF2F1	NM_002096.3	c.1205G>A	p.Arg402Gln	missense_variant	Exon 11 of 13	ENST00000394456.10	NP_002087.2
GTF2F1	XM_047438710.1	c.1232G>A	p.Arg411Gln	missense_variant	Exon 10 of 12		XP_047294666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTF2F1	ENST00000394456.10	c.1205G>A	p.Arg402Gln	missense_variant	Exon 11 of 13	1	NM_002096.3	ENSP00000377969.3
GTF2F1	ENST00000593678.5	c.953G>A	p.Arg318Gln	missense_variant	Exon 8 of 10	2		ENSP00000469091.1
GTF2F1	ENST00000594213.5	n.572G>A		non_coding_transcript_exon_variant	Exon 4 of 6	3
GTF2F1	ENST00000594965.1	n.523G>A		non_coding_transcript_exon_variant	Exon 4 of 6	3

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000626 AC: 12 AN: 191626 Hom.: 0 AF XY: 0.0000575 AC XY: 6 AN XY: 104280

Gnomad AFR exome AF: 0.000435

Gnomad AMR exome AF: 0.0000697

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000384

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000492

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000330 AC: 47 AN: 1423888 Hom.: 0 Cov.: 33 AF XY: 0.0000298 AC XY: 21 AN XY: 705732

Gnomad4 AFR exome AF: 0.000184

Gnomad4 AMR exome AF: 0.0000755

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000265

Gnomad4 OTH exome AF: 0.000119

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74488

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000121

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000666 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1205G>A (p.R402Q) alteration is located in exon 11 (coding exon 11) of the GTF2F1 gene. This alteration results from a G to A substitution at nucleotide position 1205, causing the arginine (R) at amino acid position 402 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.071	T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.085	D
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.090
Sift	Benign	0.24	T;.
Sift4G	Benign	0.41	T;T
Polyphen		0.039	B;.
Vest4		0.23
MVP		0.63
MPC		0.68
ClinPred		0.068	T
GERP RS		3.4
Varity_R		0.078
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs370397042; hg19: chr19-6380941;