Genetic Variant NM_005640.3:c.454G>A (chr18-26265280-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_005640.3(TAF4B):c.454G>A(p.Ala152Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,613,964 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A152V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0096 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 19 hom. )

Consequence

TAF4B
NM_005640.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.201

Publications

4 publications found

Variant links:

Genes affected

TAF4B (HGNC:11538): (TATA-box binding protein associated factor 4b) TATA binding protein (TBP) and TBP-associated factors (TAFs) participate in the formation of the TFIID protein complex, which is involved in initiation of transcription of genes by RNA polymerase II. This gene encodes a cell type-specific TAF that may be responsible for mediating transcription by a subset of activators in B cells. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

TAF4B Gene-Disease associations (from GenCC):

male infertility with azoospermia or oligozoospermia due to single gene mutation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
spermatogenic failure 13
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

TAF4B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024737418).

BP6

Variant 18-26265280-G-A is Benign according to our data. Variant chr18-26265280-G-A is described in ClinVar as Benign. ClinVar VariationId is 714746.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0096 (1462/152262) while in subpopulation AFR AF = 0.0326 (1356/41534). AF 95% confidence interval is 0.0312. There are 12 homozygotes in GnomAd4. There are 681 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005640.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TAF4B	NM_005640.3	MANE Select	c.454G>A	p.Ala152Thr	missense	Exon 2 of 15	NP_005631.1	Q92750-1
TAF4B	NM_001293725.2		c.454G>A	p.Ala152Thr	missense	Exon 2 of 15	NP_001280654.1	J3KTH2
TAF4B	NR_121653.2		n.943G>A		non_coding_transcript_exon	Exon 2 of 16

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TAF4B	ENST00000269142.10	TSL:1 MANE Select	c.454G>A	p.Ala152Thr	missense	Exon 2 of 15	ENSP00000269142.6	Q92750-1
TAF4B	ENST00000935352.1		c.454G>A	p.Ala152Thr	missense	Exon 2 of 16	ENSP00000605411.1
TAF4B	ENST00000935354.1		c.454G>A	p.Ala152Thr	missense	Exon 2 of 16	ENSP00000605413.1

Frequencies

GnomAD3 genomes

AF:

0.00960

AC:

1461

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00458

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:

0.000235

Gnomad OTH

AF:

0.00956

GnomAD2 exomes

AF:

0.00272

AC:

679

AN:

249372

AF XY:

0.00194

show subpopulations

Gnomad AFR exome

AF:

0.0344

Gnomad AMR exome

AF:

0.00311

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000230

Gnomad OTH exome

AF:

0.00198

GnomAD4 exome

AF:

0.00114

AC:

1662

AN:

1461702

Hom.:

Cov.:

AF XY:

0.000983

AC XY:

715

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.0350

AC:

1170

AN:

33462

American (AMR)

AF:

0.00336

AC:

150

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000152

AC:

169

AN:

1111970

Other (OTH)

AF:

0.00258

AC:

156

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

168

253

337

421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.00960

AC:

1462

AN:

152262

Hom.:

Cov.:

AF XY:

0.00915

AC XY:

681

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0326

AC:

1356

AN:

41534

American (AMR)

AF:

0.00458

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68028

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

136

204

272

340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00371

Hom.:

Bravo

AF:

0.0113

ESP6500AA

AF:

0.0277

AC:

107

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.00319

AC:

386

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.20

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.034

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.69

PhyloP100

-0.20

PrimateAI

Benign

0.23

PROVEAN

Benign

0.95

REVEL

Benign

0.092

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.049

MVP

0.27

MPC

0.036

ClinPred

0.0035

GERP RS

-10

Varity_R

0.029

gMVP

0.17

Mutation Taster

=99/1

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over