dbSNP rs1411431678: GTF2H1:p.Thr371Lys (chr11-18351939-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005316.4(GTF2H1):c.1112C>A(p.Thr371Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,444,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T371M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GTF2H1
NM_005316.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.47

Publications

0 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:

LOC105376577 (HGNC:):

LOC105376577 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3902591).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTF2H1	NM_005316.4 link	c.1112C>A	p.Thr371Lys	missense_variant	Exon 10 of 15	ENST00000265963.9	NP_005307.1	P32780-1A0A384MTQ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTF2H1	ENST00000265963.9 link	c.1112C>A	p.Thr371Lys	missense_variant	Exon 10 of 15	1	NM_005316.4	ENSP00000265963.4		P32780-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1444938

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720036

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:

33128

American (AMR)

AF:

0.00

AC:

AN:

44596

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25992

East Asian (EAS)

AF:

0.00

AC:

AN:

39466

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85918

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

9.12e-7

AC:

AN:

1096944

Other (OTH)

AF:

0.00

AC:

AN:

59800

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.006664), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.13

T;.;T;T

Eigen

Benign

0.0044

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

.;D;D;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.39

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;.;M;.

PhyloP100

5.5

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.56

T;T;T;T

Sift4G

Benign

0.92

T;T;T;T

Polyphen

0.12

B;.;B;.

Vest4

0.66

MutPred

0.39

Loss of ubiquitination at K370 (P = 0.0211);.;Loss of ubiquitination at K370 (P = 0.0211);.;

MVP

0.39

MPC

0.38

ClinPred

0.94

GERP RS

5.8

PromoterAI

0.0037

Neutral

(source)

Varity_R

0.65

gMVP

0.68

Mutation Taster

=24/76

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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