7-100107376-G-A

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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:2
• Conservation: PhyloP100: 1.50

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAF6	NM_139315.3	c.1904C>T	p.Pro635Leu	missense_variant	15/15	ENST00000453269.7
AP4M1	NM_004722.4	c.*494G>A		3_prime_UTR_variant	15/15	ENST00000359593.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAF6	ENST00000453269.7	c.1904C>T	p.Pro635Leu	missense_variant	15/15	1	NM_139315.3	P1
AP4M1	ENST00000359593.9	c.*494G>A		3_prime_UTR_variant	15/15	1	NM_004722.4	P3

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

GnomAD3 exomes AF: 0.00187 AC: 442 AN: 235872 Hom.: 10 AF XY: 0.00173 AC XY: 220 AN XY: 127214

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 SAS exome AF: 0.000250

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000236

Gnomad4 ASJ exome AF: 0.0000811

Gnomad4 EAS exome AF: 0.0260

Gnomad4 SAS exome AF: 0.000215

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000137

Gnomad4 OTH exome AF: 0.00111

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

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0197

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alazami-Yuan syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

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;.;T;T;.
Eigen	Benign	0.026
Eigen_PC	Benign	-0.047
FATHMM_MKL	Benign	0.31	N
MetaRNN	Benign	0.0053	T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.69	N;.;N;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.060	N;N;N;N;N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.033	D;D;D;D;D
Polyphen		1.0	D;.;D;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

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