Genetic Variant HEXIM1:p.Arg347Gln (chr17-45150230-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006460.3(HEXIM1):c.1040G>A(p.Arg347Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000808 in 1,609,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

HEXIM1
NM_006460.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.01

Variant links:

Genes affected

HEXIM1 (HGNC:24953): (HEXIM P-TEFb complex subunit 1) Expression of this gene is induced by hexamethylene-bis-acetamide in vascular smooth muscle cells. This gene has no introns. [provided by RefSeq, Jul 2008]

HEXIM1 links:

HEXIM2-AS1 (HGNC:55857): (HEXIM2 antisense RNA 1)

HEXIM2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09287068).

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXIM1	NM_006460.3 link	c.1040G>A	p.Arg347Gln	missense_variant	Exon 1 of 1	ENST00000332499.4	NP_006451.1	O94992
HEXIM2-AS1	NR_186788.1 link	n.768C>T		non_coding_transcript_exon_variant	Exon 2 of 2
HEXIM2-AS1	NR_186789.1 link	n.931C>T		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXIM1	ENST00000332499.4 link	c.1040G>A	p.Arg347Gln	missense_variant	Exon 1 of 1	6	NM_006460.3	ENSP00000328773.3		O94992
HEXIM2-AS1	ENST00000589950.1 link	n.*170C>T		downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000243

AC:

AN:

247134

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134756

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000197

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000755

AC:

AN:

1457376

Hom.:

Cov.:

AF XY:

0.00000967

AC XY:

AN XY:

724202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1040G>A (p.R347Q) alteration is located in exon 1 (coding exon 1) of the HEXIM1 gene. This alteration results from a G to A substitution at nucleotide position 1040, causing the arginine (R) at amino acid position 347 to be replaced by a glutamine (Q). 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

0.086

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.78

M_CAP

Benign

0.0079

MetaRNN

Benign

0.093

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.81

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.0

REVEL

Benign

0.071

Sift

Uncertain

0.0090

Sift4G

Benign

0.23

Polyphen

0.30

Vest4

0.25

MutPred

0.17

Gain of helix (P = 0.1736);

MVP

0.18

MPC

2.0

ClinPred

0.69

GERP RS

4.4

Varity_R

0.37

gMVP

0.32

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over