AP4M1 p.Phe409Leu

Variant names:

• chr7-100106747-C-A
• rs778934013
• NM_004722.4:c.1227C>A
• AP4M1 p.Phe409Leu

Your query was ambiguous. Multiple possible variants found:

• chr7-100106747-C-A
• chr7-100106747-C-G
• chr7-100106745-T-C
• chr7-100106745-TTC-CTT
• chr7-100106745-TTC-CTA
• chr7-100106745-TTC-CTG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS1_Moderate PM2 PP3_Moderate

The NM_004722.4(AP4M1):​c.1227C>A​(p.Phe409Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F409S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AP4M1 NM_004722.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.471
• Publications: 0 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: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS1: Transcript NM_004722.4 (AP4M1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

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.1227C>A	p.Phe409Leu	missense	Exon 15 of 15	NP_004713.2
	AP4M1	NM_001363671.2		c.1248C>A	p.Phe416Leu	missense	Exon 15 of 15	NP_001350600.1	C9JC87
	AP4M1	NM_001438824.1		c.1248C>A	p.Phe416Leu	missense	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.1227C>A	p.Phe409Leu	missense	Exon 15 of 15	ENSP00000352603.4	O00189
	AP4M1	ENST00000421755.5	TSL:1	c.1227C>A	p.Phe409Leu	missense	Exon 15 of 16	ENSP00000412185.1	O00189
	AP4M1	ENST00000429084.5	TSL:5	c.1248C>A	p.Phe416Leu	missense	Exon 15 of 15	ENSP00000403663.1	C9JC87

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461710 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727172

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		-0.47
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.98
gMVP		0.72
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs778934013;

hg19: chr7-99704370;