NM_004722.4:c.1002C>T

Variant names:

• chr7-100106268-C-T
• rs140843407
• NM_004722.4:c.1002C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004722.4(AP4M1):​c.1002C>T​(p.Leu334Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00836 in 1,614,108 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L334L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0068 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (207 hom.)
• Consequence: AP4M1 NM_004722.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.598
• Publications: 3 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]

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.021).
• BP6: Variant 7-100106268-C-T is Benign according to our data. Variant chr7-100106268-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.598 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0737 is higher than 0.05.

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.1002C>T	p.Leu334Leu	synonymous	Exon 13 of 15	NP_004713.2
	AP4M1	NM_001363671.2		c.1023C>T	p.Leu341Leu	synonymous	Exon 13 of 15	NP_001350600.1	C9JC87
	AP4M1	NM_001438824.1		c.1023C>T	p.Leu341Leu	synonymous	Exon 14 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.1002C>T	p.Leu334Leu	synonymous	Exon 13 of 15	ENSP00000352603.4	O00189
	AP4M1	ENST00000421755.5	TSL:1	c.1002C>T	p.Leu334Leu	synonymous	Exon 13 of 16	ENSP00000412185.1	O00189
	AP4M1	ENST00000429084.5	TSL:5	c.1023C>T	p.Leu341Leu	synonymous	Exon 13 of 15	ENSP00000403663.1	C9JC87

Frequencies

GnomAD3 genomes AF: 0.00681 AC: 1036 AN: 152210 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0296

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00765

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00551

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.0170 AC: 4275 AN: 251132 AF XY: 0.0148

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.0833

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00610

Gnomad NFE exome AF: 0.00752

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.00853 AC: 12466 AN: 1461780 Hom.: 207 Cov.: 33 AF XY: 0.00820 AC XY: 5963 AN XY: 727196

African (AFR) AF: 0.00155 AC: 52 AN: 33478

American (AMR) AF: 0.0758 AC: 3389 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000612 AC: 16 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.00934 AC: 806 AN: 86258

European-Finnish (FIN) AF: 0.00684 AC: 365 AN: 53340

Middle Eastern (MID) AF: 0.00537 AC: 31 AN: 5768

European-Non Finnish (NFE) AF: 0.00656 AC: 7299 AN: 1111990

Other (OTH) AF: 0.00831 AC: 502 AN: 60394

GnomAD4 genome AF: 0.00680 AC: 1036 AN: 152328 Hom.: 23 Cov.: 32 AF XY: 0.00644 AC XY: 480 AN XY: 74488

African (AFR) AF: 0.00224 AC: 93 AN: 41568

American (AMR) AF: 0.0295 AC: 452 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.00766 AC: 37 AN: 4830

European-Finnish (FIN) AF: 0.00546 AC: 58 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00551 AC: 375 AN: 68034

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00668 Hom.: 7

Bravo AF: 0.0107

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00654

EpiControl AF: 0.00492

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary spastic paraplegia 50 (2)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.0
DANN	Benign	0.83
PhyloP100		-0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs140843407; hg19: chr7-99703891;