18-26293530-C-T

Variant names:

• chr18-26293530-C-T
• rs587777427
• NM_005640.3:c.1831C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_005640.3(TAF4B):​c.1831C>T​(p.Arg611*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000577 in 1,386,984 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: TAF4B NM_005640.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.01925
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.54
• Publications: 4 publications found

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)

ACMG classification

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

• PP5: Variant 18-26293530-C-T is Pathogenic according to our data. Variant chr18-26293530-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 135657.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF4B	NM_005640.3	MANE Select	c.1831C>T	p.Arg611*	stop_gained splice_region	Exon 9 of 15	NP_005631.1
	TAF4B	NM_001293725.2		c.1846C>T	p.Arg616*	stop_gained splice_region	Exon 9 of 15	NP_001280654.1
	TAF4B	NR_121653.2		n.2320C>T		splice_region non_coding_transcript_exon	Exon 9 of 16

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF4B	ENST00000269142.10	TSL:1 MANE Select	c.1831C>T	p.Arg611*	stop_gained splice_region	Exon 9 of 15	ENSP00000269142.6
	TAF4B	ENST00000578121.5	TSL:2	c.1846C>T	p.Arg616*	stop_gained splice_region	Exon 9 of 15	ENSP00000462980.1
	TAF4B	ENST00000418698.3	TSL:5	n.1831C>T		splice_region non_coding_transcript_exon	Exon 9 of 16	ENSP00000389365.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000577 AC: 8 AN: 1386984 Hom.: 0 Cov.: 25 AF XY: 0.00000579 AC XY: 4 AN XY: 690630

African (AFR) AF: 0.00 AC: 0 AN: 29686

American (AMR) AF: 0.00 AC: 0 AN: 26748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23230

East Asian (EAS) AF: 0.00 AC: 0 AN: 36970

South Asian (SAS) AF: 0.00 AC: 0 AN: 74794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5496

European-Non Finnish (NFE) AF: 0.00000648 AC: 7 AN: 1080822

Other (OTH) AF: 0.0000176 AC: 1 AN: 56922

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Spermatogenic failure 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.69	D
PhyloP100		3.5
Vest4		0.86
ClinPred		1.0	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.019
dbscSNV1_RF	Benign	0.32
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777427; hg19: chr18-23873494;