Genetic Variant NM_001517.5:c.-32C>T (chr6-30908375-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_001517.5(GTF2H4):c.-32C>T 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 0.259 in 154,266 control chromosomes in the GnomAD database, including 6,097 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 0.26 ( 6021 hom., cov: 32)

Exomes 𝑓: 0.22 ( 76 hom. )

Consequence

GTF2H4
NM_001517.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.237

Publications

33 publications found

Variant links:

Genes affected

GTF2H4 (HGNC:4658): (general transcription factor IIH subunit 4) Enables RNA polymerase II general transcription initiation factor activity. Involved in transcription by RNA polymerase II. Located in nuclear speck. Part of core TFIIH complex portion of holo TFIIH complex and transcription factor TFIID complex. [provided by Alliance of Genome Resources, Apr 2022]

GTF2H4 links:

ENSG00000288473 (HGNC:):

ENSG00000288473 links:

Genome browser will be placed here

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=-0.56).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTF2H4	NM_001517.5 link	c.-32C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 14	ENST00000259895.9	NP_001508.1	Q92759-1A0A1U9X7S4
GTF2H4	NM_001517.5 link	c.-32C>T		5_prime_UTR_variant	Exon 1 of 14	ENST00000259895.9	NP_001508.1	Q92759-1A0A1U9X7S4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTF2H4	ENST00000259895.9 link	c.-32C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 14	1	NM_001517.5	ENSP00000259895.4		Q92759-1
GTF2H4	ENST00000259895.9 link	c.-32C>T		5_prime_UTR_variant	Exon 1 of 14	1	NM_001517.5	ENSP00000259895.4		Q92759-1

Frequencies

GnomAD3 genomes

AF:

0.260

AC:

39369

AN:

151698

Hom.:

6007

Cov.:

show subpopulations

Gnomad AFR

AF:

0.271

Gnomad AMI

AF:

0.297

Gnomad AMR

AF:

0.367

Gnomad ASJ

AF:

0.255

Gnomad EAS

AF:

0.606

Gnomad SAS

AF:

0.509

Gnomad FIN

AF:

0.255

Gnomad MID

AF:

0.225

Gnomad NFE

AF:

0.185

Gnomad OTH

AF:

0.255

GnomAD4 exome

AF:

0.223

AC:

547

AN:

2450

Hom.:

Cov.:

AF XY:

0.228

AC XY:

287

AN XY:

1258

show subpopulations

African (AFR)

AF:

0.210

AC:

AN:

American (AMR)

AF:

0.328

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.438

AC:

AN:

112

European-Finnish (FIN)

AF:

0.429

AC:

AN:

Middle Eastern (MID)

AF:

0.226

AC:

344

AN:

1522

European-Non Finnish (NFE)

AF:

0.104

AC:

AN:

480

Other (OTH)

AF:

0.330

AC:

AN:

194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.260

AC:

39406

AN:

151816

Hom.:

6021

Cov.:

AF XY:

0.270

AC XY:

20013

AN XY:

74174

show subpopulations

African (AFR)

AF:

0.271

AC:

11194

AN:

41380

American (AMR)

AF:

0.367

AC:

5597

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.255

AC:

886

AN:

3468

East Asian (EAS)

AF:

0.607

AC:

3133

AN:

5162

South Asian (SAS)

AF:

0.508

AC:

2423

AN:

4772

European-Finnish (FIN)

AF:

0.255

AC:

2684

AN:

10528

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.185

AC:

12598

AN:

67952

Other (OTH)

AF:

0.263

AC:

555

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1270

2540

3810

5080

6350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

410

820

1230

1640

2050

<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:

0.214

Hom.:

10084

Bravo

AF:

0.266

Asia WGS

AF:

0.551

AC:

1913

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

-0.24

PromoterAI

-0.029

Neutral

(source)

Mutation Taster

=299/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over