rs773269627

chr7-100106715-C-Achr7-100106715-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004722.4(AP4M1):c.1195C>A(p.Pro399Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P399S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AP4M1 NM_004722.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.17

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18892172).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4M1	NM_004722.4	c.1195C>A	p.Pro399Thr	missense_variant	15/15	ENST00000359593.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4M1	ENST00000359593.9	c.1195C>A	p.Pro399Thr	missense_variant	15/15	1	NM_004722.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250386 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135598

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461468 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.056	T;.;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D;.;D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	0.94	D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.19	N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.16	T;T;T;T
Sift4G	Benign	0.38	T;T;T;T
Polyphen		0.077	B;B;B;.
Vest4		0.12
MutPred		0.41		Gain of glycosylation at P406 (P = 0.0591);.;.;.;
MVP		0.85
MPC		0.13
ClinPred		0.22	T
GERP RS		4.5
Varity_R		0.19
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs773269627; hg19: chr7-99704338;