Genetic Variant HTATSF1:p.Gly76Asp (chrX-136499638-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_014500.5(HTATSF1):c.227G>A(p.Gly76Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,083,248 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000014 ( 0 hom. 6 hem. )

Failed GnomAD Quality Control

Consequence

HTATSF1
NM_014500.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.72

Variant links:

Genes affected

HTATSF1 (HGNC:5276): (HIV-1 Tat specific factor 1) The protein encoded by this gene functions as a cofactor for the stimulation of transcriptional elongation by HIV-1 Tat, which binds to the HIV-1 promoter through Tat-TAR interaction. This protein may also serve as a dual-function factor to couple transcription and splicing and to facilitate their reciprocal activation. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Sep 2009]

HTATSF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.873

BS2

High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTATSF1	NM_014500.5 link	c.227G>A	p.Gly76Asp	missense_variant	Exon 2 of 9	ENST00000218364.5	NP_055315.2	O43719
HTATSF1	NM_001163280.2 link	c.227G>A	p.Gly76Asp	missense_variant	Exon 3 of 10		NP_001156752.1	O43719

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HTATSF1	ENST00000218364.5 link	c.227G>A	p.Gly76Asp	missense_variant	Exon 2 of 9	1	NM_014500.5	ENSP00000218364.4	O43719
HTATSF1	ENST00000535601.5 link	c.227G>A	p.Gly76Asp	missense_variant	Exon 3 of 10	1		ENSP00000442699.1	O43719
HTATSF1	ENST00000448450.5 link	c.227G>A	p.Gly76Asp	missense_variant	Exon 3 of 6	5		ENSP00000411381.1	Q5H918
HTATSF1	ENST00000425695.5 link	c.227G>A	p.Gly76Asp	missense_variant	Exon 3 of 6	3		ENSP00000412420.1	Q5H919

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111745

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33949

FAILED QC

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

166008

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

53940

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000261

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000138

AC:

AN:

1083248

Hom.:

Cov.:

AF XY:

0.0000170

AC XY:

AN XY:

352242

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000179

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

111745

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33949

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000149

AC:

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

Apr 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.227G>A (p.G76D) alteration is located in exon 3 (coding exon 2) of the HTATSF1 gene. This alteration results from a G to A substitution at nucleotide position 227, causing the glycine (G) at amino acid position 76 to be replaced by an aspartic acid (D). 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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;T;T;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;.

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Benign

-0.68

MutationAssessor

Pathogenic

3.3

M;.;.;M

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.4

D;D;D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;D

Vest4

0.80

MVP

0.86

MPC

1.6

ClinPred

0.92

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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