7-100101726-A-C

Variant names:

• chr7-100101726-A-C
• rs568292146
• NM_004722.4:c.12A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004722.4(AP4M1):​c.12A>C​(p.Gln4His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,437,766 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 Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q4Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: AP4M1 NM_004722.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.68
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

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.12A>C	p.Gln4His	missense	Exon 1 of 15	NP_004713.2
	AP4M1	NM_001363671.2		c.12A>C	p.Gln4His	missense	Exon 1 of 15	NP_001350600.1	C9JC87
	AP4M1	NM_001438824.1		c.12A>C	p.Gln4His	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.12A>C	p.Gln4His	missense	Exon 1 of 15	ENSP00000352603.4	O00189
	AP4M1	ENST00000421755.5	TSL:1	c.12A>C	p.Gln4His	missense	Exon 1 of 16	ENSP00000412185.1	O00189
	MCM7	ENST00000343023.10	TSL:1	c.-432T>G		5_prime_UTR	Exon 1 of 9	ENSP00000344006.6	P33993-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437766 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 714920

African (AFR) AF: 0.00 AC: 0 AN: 32474

American (AMR) AF: 0.00 AC: 0 AN: 44144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25418

East Asian (EAS) AF: 0.00 AC: 0 AN: 38472

South Asian (SAS) AF: 0.00 AC: 0 AN: 86014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095112

Other (OTH) AF: 0.00 AC: 0 AN: 58884

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.80
MutPred		0.68		Gain of sheet (P = 0.0827)
MVP		0.84
MPC		0.50
ClinPred		0.99	D
GERP RS		2.9
PromoterAI		-0.022	Neutral
Varity_R		0.82
gMVP		0.68
Mutation Taster		=51/49	polymorphism

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: rs568292146; hg19: chr7-99699349;