Variant 19-10577202-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000250244.11(AP1M2):c.1043T>C(p.Phe348Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,752 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

AP1M2
ENST00000250244.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.39

Variant links:

Genes affected

AP1M2 (HGNC:558): (adaptor related protein complex 1 subunit mu 2) This gene encodes a subunit of the heterotetrameric adaptor-related protein comlex 1 (AP-1), which belongs to the adaptor complexes medium subunits family. This protein is capable of interacting with tyrosine-based sorting signals. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

AP1M2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
AP1M2	NM_005498.5 linkuse as main transcript	c.1043T>C	p.Phe348Ser	missense_variant	9/12	ENST00000250244.11	NP_005489.2
AP1M2	NM_001300887.2 linkuse as main transcript	c.1049T>C	p.Phe350Ser	missense_variant	9/12		NP_001287816.1
AP1M2	XM_047438018.1 linkuse as main transcript	c.971T>C	p.Phe324Ser	missense_variant	9/12		XP_047293974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP1M2	ENST00000250244.11 linkuse as main transcript	c.1043T>C	p.Phe348Ser	missense_variant	9/12	1	NM_005498.5	ENSP00000250244	P4	Q9Y6Q5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456752

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724422

show subpopulations

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:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2024

The c.1043T>C (p.F348S) alteration is located in exon 9 (coding exon 9) of the AP1M2 gene. This alteration results from a T to C substitution at nucleotide position 1043, causing the phenylalanine (F) at amino acid position 348 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.00061

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

.;.;T;T

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

T;T;T;D

M_CAP

Uncertain

0.097

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Benign

-0.67

MutationAssessor

Pathogenic

4.3

.;.;H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.2

.;.;D;.

REVEL

Uncertain

0.33

Sift

Pathogenic

0.0

.;.;D;.

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

0.55, 0.89

.;P;P;.

Vest4

0.62, 0.61

MutPred

0.82

.;.;Gain of disorder (P = 0.0089);.;

MVP

0.40

MPC

0.35

ClinPred

1.0

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.75

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over