11-18352386-T-G

Position:

• chr11-18352386-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005316.4(GTF2H1):​c.1200T>G​(p.Ile400Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GTF2H1 NM_005316.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GTF2H1	NM_005316.4	c.1200T>G	p.Ile400Met	missense_variant	11/15	ENST00000265963.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GTF2H1	ENST00000265963.9	c.1200T>G	p.Ile400Met	missense_variant	11/15	1	NM_005316.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

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

Dec 13, 2022

The c.1200T>G (p.I400M) alteration is located in exon 12 (coding exon 10) of the GTF2H1 gene. This alteration results from a T to G substitution at nucleotide position 1200, causing the isoleucine (I) at amino acid position 400 to be replaced by a methionine (M). 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	0.20
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T;.;T;T
Eigen	Benign	0.066
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.50	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.27	T;T;T;T
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.25	B;.;B;.
Vest4		0.63
MutPred		0.27		Gain of disorder (P = 0.0485);.;Gain of disorder (P = 0.0485);.;
MVP		0.50
MPC		0.31
ClinPred		0.82	D
GERP RS		4.9
Varity_R		0.30
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-18373933;