7-100101733-A-C

Variant names:

• chr7-100101733-A-C
• rs762494123
• NM_004722.4:c.19A>C

Variant summary

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

The NM_004722.4(AP4M1):​c.19A>C​(p.Ile7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,414,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I7V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AP4M1 NM_004722.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.00
• Publications: 2 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.19A>C	p.Ile7Leu	missense	Exon 1 of 15	NP_004713.2
	AP4M1	NM_001363671.2		c.19A>C	p.Ile7Leu	missense	Exon 1 of 15	NP_001350600.1	C9JC87
	AP4M1	NM_001438824.1		c.19A>C	p.Ile7Leu	missense	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.19A>C	p.Ile7Leu	missense	Exon 1 of 15	ENSP00000352603.4	O00189
	AP4M1	ENST00000421755.5	TSL:1	c.19A>C	p.Ile7Leu	missense	Exon 1 of 16	ENSP00000412185.1	O00189
	MCM7	ENST00000343023.10	TSL:1	c.-439T>G		5_prime_UTR	Exon 1 of 9	ENSP00000344006.6	P33993-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1414808 Hom.: 0 Cov.: 33 AF XY: 0.00000142 AC XY: 1 AN XY: 703206

African (AFR) AF: 0.00 AC: 0 AN: 31510

American (AMR) AF: 0.00 AC: 0 AN: 43564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24620

East Asian (EAS) AF: 0.00 AC: 0 AN: 37196

South Asian (SAS) AF: 0.00 AC: 0 AN: 85800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5502

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1079208

Other (OTH) AF: 0.00 AC: 0 AN: 57208

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.093	D
MutationAssessor	Benign	1.9	L
PhyloP100		3.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.023	D
Sift4G	Benign	0.11	T
Polyphen		0.96	D
Vest4		0.55
MutPred		0.54		Gain of catalytic residue at I7 (P = 0.0745)
MVP		0.78
MPC		0.37
ClinPred		0.96	D
GERP RS		5.7
PromoterAI		0.045	Neutral
Varity_R		0.69
gMVP		0.62
Mutation Taster		=214/86	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs762494123; hg19: chr7-99699356;