7-100113899-A-T

Variant names:

• chr7-100113899-A-T
• rs374993554
• NM_139315.3:c.212T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_139315.3(TAF6):​c.212T>A​(p.Ile71Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I71T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TAF6 NM_139315.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.42

Genes affected

TAF6 (HGNC:11540): (TATA-box binding protein associated factor 6) 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 one of the smaller subunits of TFIID that binds weakly to TBP but strongly to TAF1, the largest subunit of TFIID. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-100113899-A-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAF6	NM_139315.3	c.212T>A	p.Ile71Asn	missense_variant	Exon 3 of 15	ENST00000453269.7	NP_647476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAF6	ENST00000453269.7	c.212T>A	p.Ile71Asn	missense_variant	Exon 3 of 15	1	NM_139315.3	ENSP00000389575.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;.;D;D;.;T;.;.;T;T;T;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.8	M;.;M;M;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.9	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.;.;D;.;D;.;.;.
Polyphen		0.84	P;.;P;P;.;D;.;.;.;.;.;.;.
Vest4		0.95
MutPred		0.84		Gain of disorder (P = 0.0102);.;Gain of disorder (P = 0.0102);Gain of disorder (P = 0.0102);.;Gain of disorder (P = 0.0102);Gain of disorder (P = 0.0102);Gain of disorder (P = 0.0102);.;Gain of disorder (P = 0.0102);.;Gain of disorder (P = 0.0102);Gain of disorder (P = 0.0102);
MVP		0.85
MPC		1.7
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.97
gMVP		0.94

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

LitVar

Other links and lift over

dbSNP: rs374993554; hg19: chr7-99711522;