7-100107376-G-A

Variant names:

• chr7-100107376-G-A
• rs79147701
• NM_139315.3:c.1904C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_139315.3(TAF6):​c.1904C>T​(p.Pro635Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000782 in 1,589,858 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P635P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00078 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (20 hom.)
• Consequence: TAF6 NM_139315.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.50
• Publications: 5 publications found

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]

AP4M1 (HGNC:574): (adaptor related protein complex 4 subunit mu 1) This gene encodes a subunit of the heterotetrameric AP-4 complex. The encoded protein belongs to the adaptor complexes medium subunits family. This AP-4 complex is involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system. [provided by RefSeq, Jul 2008]

AP4M1 Gene-Disease associations (from GenCC):

• AP-4 deficiency syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 50

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• AP4-related intellectual disability and spastic paraplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005346626).
• BP6: Variant 7-100107376-G-A is Benign according to our data. Variant chr7-100107376-G-A is described in ClinVar as Benign. ClinVar VariationId is 712377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000781 (119/152346) while in subpopulation EAS AF = 0.0197 (102/5180). AF 95% confidence interval is 0.0166. There are 2 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139315.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF6	NM_139315.3	MANE Select	c.1904C>T	p.Pro635Leu	missense	Exon 15 of 15	NP_647476.1	P49848-1
	AP4M1	NM_004722.4	MANE Select	c.*494G>A		3_prime_UTR	Exon 15 of 15	NP_004713.2
	TAF6	NM_001365004.1		c.2042C>T	p.Pro681Leu	missense	Exon 16 of 16	NP_001351933.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF6	ENST00000453269.7	TSL:1 MANE Select	c.1904C>T	p.Pro635Leu	missense	Exon 15 of 15	ENSP00000389575.2	P49848-1
	TAF6	ENST00000344095.8	TSL:1	c.1904C>T	p.Pro635Leu	missense	Exon 15 of 15	ENSP00000344537.4	P49848-1
	TAF6	ENST00000452041.5	TSL:1	c.1904C>T	p.Pro635Leu	missense	Exon 15 of 15	ENSP00000416396.1	P49848-1

Frequencies

GnomAD3 genomes AF: 0.000782 AC: 119 AN: 152228 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0196

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00187 AC: 442 AN: 235872 AF XY: 0.00173

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.0000309

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0234

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000375

Gnomad OTH exome AF: 0.000698

GnomAD4 exome AF: 0.000782 AC: 1124 AN: 1437512 Hom.: 20 Cov.: 34 AF XY: 0.000763 AC XY: 543 AN XY: 711934

African (AFR) AF: 0.00 AC: 0 AN: 32910

American (AMR) AF: 0.0000236 AC: 1 AN: 42298

Ashkenazi Jewish (ASJ) AF: 0.0000811 AC: 2 AN: 24658

East Asian (EAS) AF: 0.0260 AC: 1021 AN: 39344

South Asian (SAS) AF: 0.000215 AC: 18 AN: 83650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52426

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5660

European-Non Finnish (NFE) AF: 0.0000137 AC: 15 AN: 1097362

Other (OTH) AF: 0.00111 AC: 66 AN: 59204

GnomAD4 genome AF: 0.000781 AC: 119 AN: 152346 Hom.: 2 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74494

African (AFR) AF: 0.000240 AC: 10 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0197 AC: 102 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.0000504 Hom.: 0

Bravo AF: 0.000990

ExAC AF: 0.00185 AC: 224

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Alazami-Yuan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	T
Eigen	Benign	0.026
Eigen_PC	Benign	-0.047
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.17
MVP		0.70
MPC		0.45
ClinPred		0.064	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.084
gMVP		0.14
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs79147701; hg19: chr7-99704999; COSMIC: COSV59844655; COSMIC: COSV59844655;