11-62786623-G-A

Position:

• chr11-62786623-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000294168.8(TAF6L):​c.1196G>A​(p.Ser399Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S399T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TAF6L ENST00000294168.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64

Genes affected

TAF6L (HGNC:17305): (TATA-box binding protein associated factor 6 like) Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes a protein that is a component of the PCAF histone acetylase complex and structurally similar to one of the histone-like TAFs, TAF6. The PCAF histone acetylase complex, which is composed of more than 20 polypeptides some of which are TAFs, is required for myogenic transcription and differentiation. [provided by RefSeq, Jul 2008]

TMEM223 (HGNC:28464): (transmembrane protein 223) Predicted to be involved in nervous system development. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000269176 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13986135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAF6L	NM_006473.4	c.1196G>A	p.Ser399Asn	missense_variant	11/11	ENST00000294168.8	NP_006464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAF6L	ENST00000294168.8	c.1196G>A	p.Ser399Asn	missense_variant	11/11	1	NM_006473.4	ENSP00000294168.3
TMEM223	ENST00000528367.1	c.313+5056C>T		intron_variant		2		ENSP00000431804.1
ENSG00000269176	ENST00000601484.2	n.163C>T		non_coding_transcript_exon_variant	1/1	6
TMEM223	ENST00000527073.1	n.65+5056C>T		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448742 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719714

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: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2023

The c.1196G>A (p.S399N) alteration is located in exon 11 (coding exon 10) of the TAF6L gene. This alteration results from a G to A substitution at nucleotide position 1196, causing the serine (S) at amino acid position 399 to be replaced by an asparagine (N). 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	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0031
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.74	N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.030
Sift	Benign	0.22	T
Sift4G	Uncertain	0.031	D
Polyphen		0.094	B
Vest4		0.27
MutPred		0.26		Loss of phosphorylation at S399 (P = 0.0377);
MVP		0.18
MPC		0.63
ClinPred		0.70	D
GERP RS		5.0
Varity_R		0.17
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-62554095;