chr7-100101167-C-G

Variant names:

• chr7-100101167-C-G
• rs76000357
• NM_005916.5:c.31+97G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001438825.1(AP4M1):​c.-337C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00559 in 1,516,760 control chromosomes in the GnomAD database, including 421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (212 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (209 hom.)
• Consequence: AP4M1 NM_001438825.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0280
• Publications: 1 publications found

Genes affected

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]

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]

AP4M1 Gene-Disease associations (from GenCC):

• AP-4 deficiency syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 50

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• AP4-related intellectual disability and spastic paraplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 7-100101167-C-G is Benign according to our data. Variant chr7-100101167-C-G is described in ClinVar as Benign. ClinVar VariationId is 1290038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0967 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438825.1. 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
	MCM7	NM_005916.5	MANE Select	c.31+97G>C		intron	N/A	NP_005907.3
	AP4M1	NM_001438825.1		c.-337C>G		5_prime_UTR	Exon 1 of 16	NP_001425754.1
	MCM7	NM_001439272.1		c.-291+33G>C		intron	N/A	NP_001426201.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM7	ENST00000303887.10	TSL:1 MANE Select	c.31+97G>C		intron	N/A	ENSP00000307288.5	P33993-1
	MCM7	ENST00000343023.10	TSL:1	c.31+97G>C		intron	N/A	ENSP00000344006.6	P33993-2
	MCM7	ENST00000489841.6	TSL:1	n.677+97G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 4343 AN: 152198 Hom.: 211 Cov.: 33

Gnomad AFR AF: 0.0993

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00988

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0215

GnomAD4 exome AF: 0.00302 AC: 4118 AN: 1364444 Hom.: 209 Cov.: 21 AF XY: 0.00259 AC XY: 1768 AN XY: 682932

African (AFR) AF: 0.101 AC: 3193 AN: 31634

American (AMR) AF: 0.00653 AC: 286 AN: 43780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25256

East Asian (EAS) AF: 0.00 AC: 0 AN: 39088

South Asian (SAS) AF: 0.000238 AC: 20 AN: 84036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44172

Middle Eastern (MID) AF: 0.00394 AC: 22 AN: 5582

European-Non Finnish (NFE) AF: 0.000202 AC: 209 AN: 1033808

Other (OTH) AF: 0.00680 AC: 388 AN: 57088

GnomAD4 genome AF: 0.0286 AC: 4355 AN: 152316 Hom.: 212 Cov.: 33 AF XY: 0.0271 AC XY: 2015 AN XY: 74484

African (AFR) AF: 0.0993 AC: 4127 AN: 41570

American (AMR) AF: 0.00986 AC: 151 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68022

Other (OTH) AF: 0.0213 AC: 45 AN: 2114

Alfa AF: 0.0213 Hom.: 13

Bravo AF: 0.0319

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.4
DANN	Benign	0.41
PhyloP100		0.028
PromoterAI		-0.019	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs76000357; hg19: chr7-99698790;