19-10577202-A-G

Variant names:

• chr19-10577202-A-G
• rs1917263252
• NM_005498.5:c.1043T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005498.5(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 NM_005498.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39

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]

ACMG classification

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 rank	MANE	Protein	UniProt
AP1M2	NM_005498.5	c.1043T>C	p.Phe348Ser	missense_variant	Exon 9 of 12	ENST00000250244.11	NP_005489.2
AP1M2	NM_001300887.2	c.1049T>C	p.Phe350Ser	missense_variant	Exon 9 of 12		NP_001287816.1
AP1M2	XM_047438018.1	c.971T>C	p.Phe324Ser	missense_variant	Exon 9 of 12		XP_047293974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP1M2	ENST00000250244.11	c.1043T>C	p.Phe348Ser	missense_variant	Exon 9 of 12	1	NM_005498.5	ENSP00000250244.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456752 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 724422

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.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;.;T;T
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;T;T;D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Pathogenic	4.3	.;.;H;.
PrimateAI	Pathogenic	0.86	D
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	D
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

Other links and lift over

dbSNP: rs1917263252; hg19: chr19-10687878;