chr8-119803881-G-C

Variant names:

• chr8-119803881-G-C
• rs398124656
• NM_003184.4:c.557C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003184.4(TAF2):​c.557C>G​(p.Thr186Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TAF2 NM_003184.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 9.95
• Publications: 2 publications found

Genes affected

TAF2 (HGNC:11536): (TATA-box binding protein associated factor 2) 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 larger subunits of TFIID that is stably associated with the TFIID complex. It contributes to interactions at and downstream of the transcription initiation site, interactions that help determine transcription complex response to activators. [provided by RefSeq, Jul 2008]

TAF2 Gene-Disease associations (from GenCC):

• microcephaly-thin corpus callosum-intellectual disability syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAF2	NM_003184.4	c.557C>G	p.Thr186Arg	missense_variant	Exon 5 of 26	ENST00000378164.7	NP_003175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAF2	ENST00000378164.7	c.557C>G	p.Thr186Arg	missense_variant	Exon 5 of 26	1	NM_003184.4	ENSP00000367406.2
TAF2	ENST00000686879.1	c.557C>G	p.Thr186Arg	missense_variant	Exon 5 of 27			ENSP00000509206.1
TAF2	ENST00000685235.1	c.557C>G	p.Thr186Arg	missense_variant	Exon 5 of 26			ENSP00000510174.1
TAF2	ENST00000688645.1	c.557C>G	p.Thr186Arg	missense_variant	Exon 5 of 25			ENSP00000509978.1
TAF2	ENST00000523904.2	c.557C>G	p.Thr186Arg	missense_variant	Exon 5 of 25	3		ENSP00000430832.2
TAF2	ENST00000690144.1	c.557C>G	p.Thr186Arg	missense_variant	Exon 5 of 26			ENSP00000510548.1
TAF2	ENST00000521007.2	c.557C>G	p.Thr186Arg	missense_variant	Exon 6 of 7	3		ENSP00000428484.2
TAF2	ENST00000685202.1	n.557C>G		non_coding_transcript_exon_variant	Exon 5 of 27			ENSP00000509214.1
TAF2	ENST00000685503.1	n.557C>G		non_coding_transcript_exon_variant	Exon 5 of 26			ENSP00000509198.1
TAF2	ENST00000685663.1	n.*429C>G		non_coding_transcript_exon_variant	Exon 7 of 28			ENSP00000508988.1
TAF2	ENST00000685824.1	n.*372C>G		non_coding_transcript_exon_variant	Exon 4 of 24			ENSP00000510262.1
TAF2	ENST00000685876.1	n.*275C>G		non_coding_transcript_exon_variant	Exon 6 of 27			ENSP00000510493.1
TAF2	ENST00000685993.1	n.*372C>G		non_coding_transcript_exon_variant	Exon 4 of 25			ENSP00000510102.1
TAF2	ENST00000686098.1	n.557C>G		non_coding_transcript_exon_variant	Exon 5 of 25			ENSP00000509102.1
TAF2	ENST00000689164.1	n.557C>G		non_coding_transcript_exon_variant	Exon 5 of 24			ENSP00000508729.1
TAF2	ENST00000689919.1	n.*275C>G		non_coding_transcript_exon_variant	Exon 6 of 26			ENSP00000510768.1
TAF2	ENST00000690808.1	n.557C>G		non_coding_transcript_exon_variant	Exon 5 of 26			ENSP00000509791.1
TAF2	ENST00000690922.1	n.557C>G		non_coding_transcript_exon_variant	Exon 5 of 26			ENSP00000509498.1
TAF2	ENST00000691880.1	n.*213C>G		non_coding_transcript_exon_variant	Exon 4 of 25			ENSP00000508515.1
TAF2	ENST00000692518.1	n.*372C>G		non_coding_transcript_exon_variant	Exon 4 of 25			ENSP00000508959.1
TAF2	ENST00000692707.1	n.*275C>G		non_coding_transcript_exon_variant	Exon 6 of 28			ENSP00000509024.1
TAF2	ENST00000685663.1	n.*429C>G		3_prime_UTR_variant	Exon 7 of 28			ENSP00000508988.1
TAF2	ENST00000685824.1	n.*372C>G		3_prime_UTR_variant	Exon 4 of 24			ENSP00000510262.1
TAF2	ENST00000685876.1	n.*275C>G		3_prime_UTR_variant	Exon 6 of 27			ENSP00000510493.1
TAF2	ENST00000685993.1	n.*372C>G		3_prime_UTR_variant	Exon 4 of 25			ENSP00000510102.1
TAF2	ENST00000689919.1	n.*275C>G		3_prime_UTR_variant	Exon 6 of 26			ENSP00000510768.1
TAF2	ENST00000691880.1	n.*213C>G		3_prime_UTR_variant	Exon 4 of 25			ENSP00000508515.1
TAF2	ENST00000692518.1	n.*372C>G		3_prime_UTR_variant	Exon 4 of 25			ENSP00000508959.1
TAF2	ENST00000692707.1	n.*275C>G		3_prime_UTR_variant	Exon 6 of 28			ENSP00000509024.1
TAF2	ENST00000685684.1	n.520+37C>G		intron_variant	Intron 5 of 24			ENSP00000509441.1
TAF2	ENST00000688037.1	n.139-1856C>G		intron_variant	Intron 2 of 22			ENSP00000510169.1
TAF2	ENST00000690031.1	n.*238+37C>G		intron_variant	Intron 6 of 9			ENSP00000508549.1
TAF2	ENST00000691847.1	n.538+19C>G		intron_variant	Intron 5 of 23			ENSP00000509663.1
TAF2	ENST00000692916.1	n.419-1856C>G		intron_variant	Intron 4 of 24			ENSP00000509603.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microcephaly-thin corpus callosum-intellectual disability syndrome Uncertain:1

Dec 01, 2013

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		9.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.77	P
Vest4		0.89
MutPred		0.81		Gain of MoRF binding (P = 0.1401);
MVP		0.28
MPC		0.97
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.81
gMVP		0.95
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 37

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

Other links and lift over

dbSNP: rs398124656; hg19: chr8-120816121;