chr11-18341391-T-G

Position:

• chr11-18341391-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005316.4(GTF2H1):​c.738T>G​(p.Cys246Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GTF2H1 NM_005316.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.64

Genes affected

GTF2H1 (HGNC:4655): (general transcription factor IIH subunit 1) Enables thyroid hormone receptor binding activity. Involved in positive regulation of transcription, DNA-templated and transcription by RNA polymerase II. Located in nucleoplasm. Part of transcription factor TFIIH core complex and transcription factor TFIIH holo complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GTF2H1	NM_005316.4	c.738T>G	p.Cys246Trp	missense_variant	6/15	ENST00000265963.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GTF2H1	ENST00000265963.9	c.738T>G	p.Cys246Trp	missense_variant	6/15	1	NM_005316.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461602 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727094

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The c.738T>G (p.C246W) alteration is located in exon 7 (coding exon 5) of the GTF2H1 gene. This alteration results from a T to G substitution at nucleotide position 738, causing the cysteine (C) at amino acid position 246 to be replaced by a tryptophan (W). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;.;D;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.9	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-9.7	D;D;D;D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.85
MutPred		0.59		Loss of ubiquitination at K248 (P = 0.1016);.;Loss of ubiquitination at K248 (P = 0.1016);.;
MVP		0.70
MPC		1.1
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.92

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: rs1865152177; hg19: chr11-18362938;