chr18-26293530-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP7

The NM_005640.3(TAF4B):​c.1831C>A​(p.Arg611Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,538,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TAF4B NM_005640.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.00003660
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP7: Synonymous conserved (PhyloP=3.54 with no splicing effect.

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>A	p.Arg611Arg	splice_region synonymous	Exon 9 of 15	NP_005631.1
	TAF4B	NM_001293725.2		c.1846C>A	p.Arg616Arg	splice_region synonymous	Exon 9 of 15	NP_001280654.1
	TAF4B	NR_121653.2		n.2320C>A		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>A	p.Arg611Arg	splice_region synonymous	Exon 9 of 15	ENSP00000269142.6
	TAF4B	ENST00000578121.5	TSL:2	c.1846C>A	p.Arg616Arg	splice_region synonymous	Exon 9 of 15	ENSP00000462980.1
	TAF4B	ENST00000418698.3	TSL:5	n.1831C>A		splice_region non_coding_transcript_exon	Exon 9 of 16	ENSP00000389365.3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151898 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000101 AC: 14 AN: 1386978 Hom.: 0 Cov.: 25 AF XY: 0.00000434 AC XY: 3 AN XY: 690626

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.0000374 AC: 1 AN: 26748

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

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 36970

South Asian (SAS) AF: 0.00 AC: 0 AN: 74792

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: 0.0000102 AC: 11 AN: 1080818

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000109461), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151898 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74184

African (AFR) AF: 0.0000242 AC: 1 AN: 41356

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.066
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

Other links and lift over

dbSNP: rs587777427; hg19: chr18-23873494;