2-27337941-T-A

Variant names:

• chr2-27337941-T-A
• rs780428734
• NM_001035521.3:c.935A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001035521.3(GTF3C2):​c.935A>T​(p.His312Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H312R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GTF3C2 NM_001035521.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83
• Publications: 0 publications found

Genes affected

GTF3C2 (HGNC:4665): (general transcription factor IIIC subunit 2) Contributes to DNA binding activity. Involved in transcription by RNA polymerase III. Located in nucleoplasm. Part of transcription factor TFIIIC complex. [provided by Alliance of Genome Resources, Apr 2022]

GTF3C2-AS1 (HGNC:40269): (GTF3C2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32526618).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035521.3. 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
	GTF3C2	NM_001035521.3	MANE Select	c.935A>T	p.His312Leu	missense	Exon 5 of 19	NP_001030598.1	Q8WUA4-1
	GTF3C2	NM_001318909.4		c.935A>T	p.His312Leu	missense	Exon 5 of 19	NP_001305838.2	Q8WUA4-1
	GTF3C2	NM_001388380.3		c.935A>T	p.His312Leu	missense	Exon 6 of 20	NP_001375309.2	Q8WUA4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTF3C2	ENST00000264720.8	TSL:1 MANE Select	c.935A>T	p.His312Leu	missense	Exon 5 of 19	ENSP00000264720.3	Q8WUA4-1
	GTF3C2	ENST00000359541.6	TSL:1	c.935A>T	p.His312Leu	missense	Exon 5 of 19	ENSP00000352536.2	Q8WUA4-1
	GTF3C2	ENST00000957129.1		c.935A>T	p.His312Leu	missense	Exon 5 of 19	ENSP00000627188.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449332 Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1 AN XY: 721934

African (AFR) AF: 0.00 AC: 0 AN: 33244

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 85996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100562

Other (OTH) AF: 0.00 AC: 0 AN: 59982

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.069
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.8
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.26
Sift	Benign	0.045	D
Sift4G	Uncertain	0.023	D
Polyphen		0.65	P
Vest4		0.50
MutPred		0.42		Gain of sheet (P = 0.0036)
MVP		0.25
MPC		0.27
ClinPred		0.49	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.33
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs780428734; hg19: chr2-27560808;