chr7-100106825-C-T

Variant names:

• chr7-100106825-C-T
• rs4134932
• NM_004722.4:c.1305C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004722.4(AP4M1):​c.1305C>T​(p.Asn435Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0286 in 1,613,992 control chromosomes in the GnomAD database, including 834 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (44 hom., cov: 32)
  • Exomes 𝑓: 0.030 (790 hom.)
• Consequence: AP4M1 NM_004722.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.27
• Publications: 9 publications found

Genes affected

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]

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]

TAF6 Gene-Disease associations (from GenCC):

• Alazami-Yuan syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.1).
• BP6: Variant 7-100106825-C-T is Benign according to our data. Variant chr7-100106825-C-T is described in ClinVar as Benign. ClinVar VariationId is 128404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.27 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0184 (2800/152344) while in subpopulation NFE AF = 0.0299 (2031/68030). AF 95% confidence interval is 0.0288. There are 44 homozygotes in GnomAd4. There are 1333 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004722.4. 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
	AP4M1	NM_004722.4	MANE Select	c.1305C>T	p.Asn435Asn	synonymous	Exon 15 of 15	NP_004713.2
	AP4M1	NM_001363671.2		c.1326C>T	p.Asn442Asn	synonymous	Exon 15 of 15	NP_001350600.1	C9JC87
	AP4M1	NM_001438824.1		c.1326C>T	p.Asn442Asn	synonymous	Exon 16 of 16	NP_001425753.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4M1	ENST00000359593.9	TSL:1 MANE Select	c.1305C>T	p.Asn435Asn	synonymous	Exon 15 of 15	ENSP00000352603.4	O00189
	AP4M1	ENST00000421755.5	TSL:1	c.1305C>T	p.Asn435Asn	synonymous	Exon 15 of 16	ENSP00000412185.1	O00189
	AP4M1	ENST00000429084.5	TSL:5	c.1326C>T	p.Asn442Asn	synonymous	Exon 15 of 15	ENSP00000403663.1	C9JC87

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2802 AN: 152226 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.00622

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00838

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0299

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.0191 AC: 4794 AN: 251092 AF XY: 0.0204

Gnomad AFR exome AF: 0.00573

Gnomad AMR exome AF: 0.00787

Gnomad ASJ exome AF: 0.0202

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0150

Gnomad NFE exome AF: 0.0272

Gnomad OTH exome AF: 0.0227

GnomAD4 exome AF: 0.0296 AC: 43296 AN: 1461648 Hom.: 790 Cov.: 34 AF XY: 0.0296 AC XY: 21519 AN XY: 727142

African (AFR) AF: 0.00484 AC: 162 AN: 33480

American (AMR) AF: 0.00823 AC: 368 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 533 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0246 AC: 2126 AN: 86256

European-Finnish (FIN) AF: 0.0160 AC: 851 AN: 53186

Middle Eastern (MID) AF: 0.0165 AC: 95 AN: 5768

European-Non Finnish (NFE) AF: 0.0336 AC: 37392 AN: 1112004

Other (OTH) AF: 0.0292 AC: 1766 AN: 60394

GnomAD4 genome AF: 0.0184 AC: 2800 AN: 152344 Hom.: 44 Cov.: 32 AF XY: 0.0179 AC XY: 1333 AN XY: 74486

African (AFR) AF: 0.00620 AC: 258 AN: 41598

American (AMR) AF: 0.00837 AC: 128 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0201 AC: 97 AN: 4822

European-Finnish (FIN) AF: 0.0135 AC: 143 AN: 10630

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0299 AC: 2031 AN: 68030

Other (OTH) AF: 0.0137 AC: 29 AN: 2110

Alfa AF: 0.0254 Hom.: 131

Bravo AF: 0.0179

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0308

EpiControl AF: 0.0286

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 50 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	6.9
DANN	Benign	0.88
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs4134932; hg19: chr7-99704448; COSMIC: COSV57994651; COSMIC: COSV57994651;