rs1554380391

Variant names:

• chr7-100105461-A-C
• rs1554380391
• NM_004722.4:c.851A>C

Your query was ambiguous. Multiple possible variants found:

• chr7-100105461-A-C
• chr7-100105461-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_004722.4(AP4M1):​c.851A>C​(p.Tyr284Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AP4M1 NM_004722.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.61

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 7-100105461-A-C is Pathogenic according to our data. Variant chr7-100105461-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 471069.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4M1	NM_004722.4	c.851A>C	p.Tyr284Ser	missense_variant	Exon 11 of 15	ENST00000359593.9	NP_004713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP4M1	ENST00000359593.9	c.851A>C	p.Tyr284Ser	missense_variant	Exon 11 of 15	1	NM_004722.4	ENSP00000352603.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461840 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Pathogenic:1

Oct 01, 2020

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary spastic paraplegia 50 Pathogenic:1

Mar 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 284 of the AP4M1 protein (p.Tyr284Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 32979048; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 471069). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AP4M1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T;.;T;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;D;.;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.4	.;.;M;.;M;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-8.6	D;D;D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;D;.;.
Vest4		0.97, 0.97, 0.98
MutPred		0.88		.;Gain of disorder (P = 0.0016);.;.;.;.;.;
MVP		0.81
MPC		0.62
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554380391; hg19: chr7-99703084;