7-100107269-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_139315.3(TAF6):c.2011G>A(p.Gly671Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,523,096 control chromosomes in the GnomAD database, including 21 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (19 hom.)
• Consequence: TAF6 NM_139315.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.161

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041299164).
• BP6: Variant 7-100107269-C-T is Benign according to our data. Variant chr7-100107269-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 781652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.2011G>A	p.Gly671Ser	missense_variant	15/15	ENST00000453269.7
AP4M1	NM_004722.4	c.*387C>T		3_prime_UTR_variant	15/15	ENST00000359593.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAF6	ENST00000453269.7	c.2011G>A	p.Gly671Ser	missense_variant	15/15	1	NM_139315.3	P1
AP4M1	ENST00000359593.9	c.*387C>T		3_prime_UTR_variant	15/15	1	NM_004722.4	P3

Frequencies

GnomAD3 genomes AF: 0.00328 AC: 499 AN: 152194 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00413

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.00367 AC: 651 AN: 177194 Hom.: 3 AF XY: 0.00381 AC XY: 357 AN XY: 93702

Gnomad AFR exome AF: 0.000480

Gnomad AMR exome AF: 0.00743

Gnomad ASJ exome AF: 0.0164

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000680

Gnomad FIN exome AF: 0.000593

Gnomad NFE exome AF: 0.00450

Gnomad OTH exome AF: 0.00470

GnomAD4 exome AF: 0.00416 AC: 5702 AN: 1370784 Hom.: 19 Cov.: 34 AF XY: 0.00422 AC XY: 2835 AN XY: 672532

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00695

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00102

Gnomad4 FIN exome AF: 0.000703

Gnomad4 NFE exome AF: 0.00428

Gnomad4 OTH exome AF: 0.00535

GnomAD4 genome AF: 0.00328 AC: 499 AN: 152312 Hom.: 2 Cov.: 32 AF XY: 0.00307 AC XY: 229 AN XY: 74490

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.0207

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00413

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00441 Hom.: 0

Bravo AF: 0.00364

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000459 AC: 2

ESP6500EA AF: 0.00514 AC: 44

ExAC AF: 0.00341 AC: 405

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	AP4M1: BS2; TAF6: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 15, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.039	T;.;T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.056	N
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.0041	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;.;N;N;.
MutationTaster	Benign	0.87	D;N;N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.040	N;N;N;N;N
REVEL	Benign	0.015
Sift	Benign	0.12	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.47	P;.;P;P;.
Vest4		0.15
MVP		0.27
MPC		0.47
ClinPred		0.0080	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.15

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: rs146348021; hg19: chr7-99704892; COSMIC: COSV59841297; COSMIC: COSV59841297;