Genetic Variant GTF2H3:c.365-739C>T (chr12-123650255-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001516.5(GTF2H3):c.365-739C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0517 in 152,260 control chromosomes in the GnomAD database, including 265 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 0.052 ( 265 hom., cov: 32)

Exomes 𝑓: 0.040 ( 0 hom. )

Consequence

GTF2H3
NM_001516.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.285

Publications

9 publications found

Variant links:

Genes affected

GTF2H3 (HGNC:4657): (general transcription factor IIH subunit 3) This gene encodes a member of the TFB4 family. The encoded protein is a subunit of the core-TFIIH basal transcription factor and localizes to the nucleus. The encoded protein is involved in RNA transcription by RNA polymerase II and nucleotide excision repair and associates with the Cdk-activating kinase complex. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 14. [provided by RefSeq, Dec 2012]

GTF2H3 links:

ENSG00000279953 (HGNC:):

ENSG00000279953 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=-0.88).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
GTF2H3	NM_001516.5 link	c.365-739C>T	intron_variant	Intron 4 of 12	ENST00000543341.7	NP_001507.2
GTF2H3	NM_001271867.2 link	c.242-739C>T	intron_variant	Intron 3 of 11		NP_001258796.1
GTF2H3	NM_001271866.2 link	c.365-739C>T	intron_variant	Intron 4 of 10		NP_001258795.1
GTF2H3	NM_001271868.2 link	c.-74-739C>T	intron_variant	Intron 3 of 11		NP_001258797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTF2H3	ENST00000543341.7 link	c.365-739C>T		intron_variant	Intron 4 of 12	1	NM_001516.5	ENSP00000445162.1

Frequencies

GnomAD3 genomes

AF:

0.0518

AC:

7880

AN:

152092

Hom.:

265

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0179

Gnomad AMI

AF:

0.118

Gnomad AMR

AF:

0.0550

Gnomad ASJ

AF:

0.0254

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0155

Gnomad FIN

AF:

0.0345

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0819

Gnomad OTH

AF:

0.0427

GnomAD4 exome

AF:

0.0400

AC:

AN:

Hom.:

Cov.:

AF XY:

0.0238

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0556

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0517

AC:

7876

AN:

152210

Hom.:

265

Cov.:

AF XY:

0.0483

AC XY:

3593

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0178

AC:

740

AN:

41542

American (AMR)

AF:

0.0549

AC:

839

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0254

AC:

AN:

3470

East Asian (EAS)

AF:

0.000773

AC:

AN:

5176

South Asian (SAS)

AF:

0.0151

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0345

AC:

366

AN:

10594

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0819

AC:

5567

AN:

68008

Other (OTH)

AF:

0.0422

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

377

754

1131

1508

1885

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<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:

0.0681

Hom.:

750

Bravo

AF:

0.0528

Asia WGS

AF:

0.00779

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.4

(source)

DANN

Benign

0.78

PhyloP100

-0.28

Mutation Taster

=100/0

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