rs149661783

Variant names:

• chr7-100101771-C-A
• rs149661783
• NM_004722.4:c.57C>A

Your query was ambiguous. Multiple possible variants found:

• chr7-100101771-C-A
• chr7-100101771-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004722.4(AP4M1):​c.57C>A​(p.Asp19Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000734 in 1,362,670 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. D19N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: AP4M1 NM_004722.4 missense, splice_region
• Scores: Splicing: ADA: 0.1569
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.89
• 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]

MCM7 (HGNC:6950): (minichromosome maintenance complex component 7) The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. The hexameric protein complex formed by the MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. The MCM complex consisting of this protein and MCM2, 4 and 6 proteins possesses DNA helicase activity, and may act as a DNA unwinding enzyme. Cyclin D1-dependent kinase, CDK4, is found to associate with this protein, and may regulate the binding of this protein with the tumorsuppressor protein RB1/RB. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.57C>A	p.Asp19Glu	missense splice_region	Exon 1 of 15	NP_004713.2
	AP4M1	NM_001363671.2		c.57C>A	p.Asp19Glu	missense splice_region	Exon 1 of 15	NP_001350600.1	C9JC87
	AP4M1	NM_001438824.1		c.57C>A	p.Asp19Glu	missense splice_region	Exon 2 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.57C>A	p.Asp19Glu	missense splice_region	Exon 1 of 15	ENSP00000352603.4	O00189
	AP4M1	ENST00000421755.5	TSL:1	c.57C>A	p.Asp19Glu	missense splice_region	Exon 1 of 16	ENSP00000412185.1	O00189
	MCM7	ENST00000343023.10	TSL:1	c.-477G>T		5_prime_UTR	Exon 1 of 9	ENSP00000344006.6	P33993-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.34e-7 AC: 1 AN: 1362670 Hom.: 0 Cov.: 34 AF XY: 0.00000148 AC XY: 1 AN XY: 677716

African (AFR) AF: 0.00 AC: 0 AN: 29402

American (AMR) AF: 0.00 AC: 0 AN: 42552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23112

East Asian (EAS) AF: 0.00 AC: 0 AN: 35202

South Asian (SAS) AF: 0.00 AC: 0 AN: 85190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5334

European-Non Finnish (NFE) AF: 9.60e-7 AC: 1 AN: 1042008

Other (OTH) AF: 0.00 AC: 0 AN: 53944

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.045	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.026	D
Sift4G	Benign	0.091	T
Polyphen		1.0	D
Vest4		0.68
MutPred		0.69		Gain of methylation at K18 (P = 0.1251)
MVP		0.85
MPC		0.18
ClinPred		0.98	D
GERP RS		4.8
PromoterAI		0.024	Neutral
Varity_R		0.67
gMVP		0.47
Mutation Taster		=27/73	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.16
dbscSNV1_RF	Benign	0.48
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: rs149661783; hg19: chr7-99699394;