8-119783548-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_003184.4(TAF2):c.1945T>C(p.Trp649Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TAF2
NM_003184.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.46

Publications

2 publications found

Variant links:

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

TAF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

PP5

Variant 8-119783548-A-G is Pathogenic according to our data. Variant chr8-119783548-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 92249.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAF2	NM_003184.4 link	c.1945T>C	p.Trp649Arg	missense_variant	Exon 16 of 26	ENST00000378164.7	NP_003175.2	Q6P1X5B3KMD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TAF2	ENST00000378164.7 link	c.1945T>C	p.Trp649Arg	missense_variant	Exon 16 of 26	1	NM_003184.4	ENSP00000367406.2	Q6P1X5
TAF2	ENST00000686879.1 link	c.1945T>C	p.Trp649Arg	missense_variant	Exon 16 of 27			ENSP00000509206.1	A0A8I5KV60
TAF2	ENST00000685235.1 link	c.1945T>C	p.Trp649Arg	missense_variant	Exon 16 of 26			ENSP00000510174.1	A0A8I5QJR0
TAF2	ENST00000688645.1 link	c.1945T>C	p.Trp649Arg	missense_variant	Exon 16 of 25			ENSP00000509978.1	A0A8I5KSY6
TAF2	ENST00000523904.2 link	c.1831T>C	p.Trp611Arg	missense_variant	Exon 15 of 25	3		ENSP00000430832.2	H0YC37
TAF2	ENST00000690144.1 link	c.1945T>C	p.Trp649Arg	missense_variant	Exon 16 of 26			ENSP00000510548.1	A0A8I5KUQ2
TAF2	ENST00000685202.1 link	n.1945T>C		non_coding_transcript_exon_variant	Exon 16 of 27			ENSP00000509214.1	A0A8I5QJD7
TAF2	ENST00000685503.1 link	n.*1337T>C		non_coding_transcript_exon_variant	Exon 16 of 26			ENSP00000509198.1	A0A8I5KXS3
TAF2	ENST00000685663.1 link	n.*1817T>C		non_coding_transcript_exon_variant	Exon 18 of 28			ENSP00000508988.1	A0A8I5KUD2
TAF2	ENST00000685684.1 link	n.*3412T>C		non_coding_transcript_exon_variant	Exon 15 of 25			ENSP00000509441.1	A0A8I5KY57
TAF2	ENST00000685824.1 link	n.*1646T>C		non_coding_transcript_exon_variant	Exon 14 of 24			ENSP00000510262.1	A0A8I5KU60
TAF2	ENST00000685876.1 link	n.*1663T>C		non_coding_transcript_exon_variant	Exon 17 of 27			ENSP00000510493.1	A0A8I5KUD2
TAF2	ENST00000685993.1 link	n.*1760T>C		non_coding_transcript_exon_variant	Exon 15 of 25			ENSP00000510102.1	A0A8I5KU60
TAF2	ENST00000686098.1 link	n.*590T>C		non_coding_transcript_exon_variant	Exon 15 of 25			ENSP00000509102.1	A0A8I5KXP3
TAF2	ENST00000688037.1 link	n.*1364T>C		non_coding_transcript_exon_variant	Exon 13 of 23			ENSP00000510169.1	A0A8I5KRI4
TAF2	ENST00000689164.1 link	n.*590T>C		non_coding_transcript_exon_variant	Exon 14 of 24			ENSP00000508729.1	A0A8I5KR26
TAF2	ENST00000689919.1 link	n.*1663T>C		non_coding_transcript_exon_variant	Exon 17 of 26			ENSP00000510768.1	A0A8I5KUD2
TAF2	ENST00000690808.1 link	n.*1181T>C		non_coding_transcript_exon_variant	Exon 16 of 26			ENSP00000509791.1	A0A8I5KVC1
TAF2	ENST00000690922.1 link	n.*357T>C		non_coding_transcript_exon_variant	Exon 16 of 26			ENSP00000509498.1	A0A8I5KPW0
TAF2	ENST00000691847.1 link	n.*1246T>C		non_coding_transcript_exon_variant	Exon 15 of 24			ENSP00000509663.1	A0A8I5QJJ6
TAF2	ENST00000691880.1 link	n.*1601T>C		non_coding_transcript_exon_variant	Exon 15 of 25			ENSP00000508515.1	A0A8I5KNG3
TAF2	ENST00000692518.1 link	n.*1646T>C		non_coding_transcript_exon_variant	Exon 14 of 25			ENSP00000508959.1	A0A8I5KU60
TAF2	ENST00000692707.1 link	n.*1813T>C		non_coding_transcript_exon_variant	Exon 18 of 28			ENSP00000509024.1	A0A8I5KUD2
TAF2	ENST00000692916.1 link	n.*1332T>C		non_coding_transcript_exon_variant	Exon 15 of 25			ENSP00000509603.1	A0A8I5QJI9
TAF2	ENST00000685503.1 link	n.*1337T>C		3_prime_UTR_variant	Exon 16 of 26			ENSP00000509198.1	A0A8I5KXS3
TAF2	ENST00000685663.1 link	n.*1817T>C		3_prime_UTR_variant	Exon 18 of 28			ENSP00000508988.1	A0A8I5KUD2
TAF2	ENST00000685684.1 link	n.*3412T>C		3_prime_UTR_variant	Exon 15 of 25			ENSP00000509441.1	A0A8I5KY57
TAF2	ENST00000685824.1 link	n.*1646T>C		3_prime_UTR_variant	Exon 14 of 24			ENSP00000510262.1	A0A8I5KU60
TAF2	ENST00000685876.1 link	n.*1663T>C		3_prime_UTR_variant	Exon 17 of 27			ENSP00000510493.1	A0A8I5KUD2
TAF2	ENST00000685993.1 link	n.*1760T>C		3_prime_UTR_variant	Exon 15 of 25			ENSP00000510102.1	A0A8I5KU60
TAF2	ENST00000686098.1 link	n.*590T>C		3_prime_UTR_variant	Exon 15 of 25			ENSP00000509102.1	A0A8I5KXP3
TAF2	ENST00000688037.1 link	n.*1364T>C		3_prime_UTR_variant	Exon 13 of 23			ENSP00000510169.1	A0A8I5KRI4
TAF2	ENST00000689164.1 link	n.*590T>C		3_prime_UTR_variant	Exon 14 of 24			ENSP00000508729.1	A0A8I5KR26
TAF2	ENST00000689919.1 link	n.*1663T>C		3_prime_UTR_variant	Exon 17 of 26			ENSP00000510768.1	A0A8I5KUD2
TAF2	ENST00000690808.1 link	n.*1181T>C		3_prime_UTR_variant	Exon 16 of 26			ENSP00000509791.1	A0A8I5KVC1
TAF2	ENST00000690922.1 link	n.*357T>C		3_prime_UTR_variant	Exon 16 of 26			ENSP00000509498.1	A0A8I5KPW0
TAF2	ENST00000691847.1 link	n.*1246T>C		3_prime_UTR_variant	Exon 15 of 24			ENSP00000509663.1	A0A8I5QJJ6
TAF2	ENST00000691880.1 link	n.*1601T>C		3_prime_UTR_variant	Exon 15 of 25			ENSP00000508515.1	A0A8I5KNG3
TAF2	ENST00000692518.1 link	n.*1646T>C		3_prime_UTR_variant	Exon 14 of 25			ENSP00000508959.1	A0A8I5KU60
TAF2	ENST00000692707.1 link	n.*1813T>C		3_prime_UTR_variant	Exon 18 of 28			ENSP00000509024.1	A0A8I5KUD2
TAF2	ENST00000692916.1 link	n.*1332T>C		3_prime_UTR_variant	Exon 15 of 25			ENSP00000509603.1	A0A8I5QJI9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727228

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Microcephaly-thin corpus callosum-intellectual disability syndrome

Pathogenic:1

Sep 21, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

-0.12

MutationAssessor

Pathogenic

3.2

PhyloP100

7.5

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-12

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.77

Gain of helix (P = 0.027);

MVP

0.76

MPC

1.7

ClinPred

0.98

GERP RS

6.1

Varity_R

0.95

gMVP

0.91

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over