Genetic Variant GTF2H1:c.-446T>C (chr11-18322517-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000453096.6(GTF2H1):c.-446T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 152,148 control chromosomes in the GnomAD database, including 15,517 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.42 ( 15491 hom., cov: 31)

Exomes 𝑓: 0.59 ( 26 hom. )

Consequence

GTF2H1
ENST00000453096.6 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.519

Publications

24 publications found

Variant links:

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]

GTF2H1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
GTF2H1	NM_005316.4 link	c.-239T>C	upstream_gene_variant	ENST00000265963.9	NP_005307.1
GTF2H1	NM_001142307.2 link	c.-446T>C	upstream_gene_variant		NP_001135779.1
GTF2H1	XM_006718208.4 link	c.-300T>C	upstream_gene_variant		XP_006718271.1
GTF2H1	XM_024448457.2 link	c.-507T>C	upstream_gene_variant		XP_024304225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTF2H1	ENST00000265963.9 link	c.-239T>C		upstream_gene_variant		1	NM_005316.4	ENSP00000265963.4

Frequencies

GnomAD3 genomes

AF:

0.417

AC:

63319

AN:

151892

Hom.:

15491

Cov.:

show subpopulations

Gnomad AFR

AF:

0.148

Gnomad AMI

AF:

0.646

Gnomad AMR

AF:

0.481

Gnomad ASJ

AF:

0.367

Gnomad EAS

AF:

0.587

Gnomad SAS

AF:

0.403

Gnomad FIN

AF:

0.517

Gnomad MID

AF:

0.318

Gnomad NFE

AF:

0.539

Gnomad OTH

AF:

0.405

GnomAD4 exome

AF:

0.587

AC:

AN:

138

Hom.:

Cov.:

AF XY:

0.587

AC XY:

AN XY:

104

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

1.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.667

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

1.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.574

AC:

AN:

122

Other (OTH)

AF:

0.750

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.417

AC:

63326

AN:

152010

Hom.:

15491

Cov.:

AF XY:

0.417

AC XY:

30987

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.148

AC:

6143

AN:

41488

American (AMR)

AF:

0.481

AC:

7354

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.367

AC:

1275

AN:

3470

East Asian (EAS)

AF:

0.587

AC:

3023

AN:

5152

South Asian (SAS)

AF:

0.404

AC:

1943

AN:

4810

European-Finnish (FIN)

AF:

0.517

AC:

5467

AN:

10574

Middle Eastern (MID)

AF:

0.325

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.539

AC:

36583

AN:

67916

Other (OTH)

AF:

0.404

AC:

854

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1681

3363

5044

6726

8407

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

570

1140

1710

2280

2850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.478

Hom.:

41849

Bravo

AF:

0.404

Asia WGS

AF:

0.456

AC:

1585

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

9.9

(source)

DANN

Benign

0.83

PhyloP100

0.52

PromoterAI

0.025

Neutral

(source)

Mutation Taster

=293/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over