NM_004069.6:c.44G>T

Variant names:

• chr19-46846102-C-A
• rs397514499
• NM_004069.6:c.44G>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004069.6(AP2S1):​c.44G>T​(p.Arg15Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: AP2S1 NM_004069.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.23
• Publications: 31 publications found

Genes affected

AP2S1 (HGNC:565): (adaptor related protein complex 2 subunit sigma 1) One of two major clathrin-associated adaptor complexes, AP-2, is a heterotetramer which is associated with the plasma membrane. This complex is composed of two large chains, a medium chain, and a small chain. This gene encodes the small chain of this complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

AP2S1 Gene-Disease associations (from GenCC):

• familial hypocalciuric hypercalcemia 3

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-46846102-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 39426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 19-46846102-C-A is Pathogenic according to our data. Variant chr19-46846102-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 39425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004069.6. 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
	AP2S1	NM_004069.6	MANE Select	c.44G>T	p.Arg15Leu	missense	Exon 2 of 5	NP_004060.2	P53680-1
	AP2S1	NM_001301076.3		c.92G>T	p.Arg31Leu	missense	Exon 2 of 5	NP_001288005.1	M0QYZ2
	AP2S1	NM_001301078.3		c.44G>T	p.Arg15Leu	missense	Exon 2 of 5	NP_001288007.1	X6R390

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP2S1	ENST00000263270.11	TSL:1 MANE Select	c.44G>T	p.Arg15Leu	missense	Exon 2 of 5	ENSP00000263270.6	P53680-1
	AP2S1	ENST00000597020.5	TSL:1	c.-17G>T		5_prime_UTR	Exon 1 of 4	ENSP00000470235.1	M0QZ21
	AP2S1	ENST00000960448.1		c.44G>T	p.Arg15Leu	missense	Exon 2 of 6	ENSP00000630507.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Familial hypocalciuric hypercalcemia 3 (4)
4	-	-	not provided (4)
1	-	-	AP2S1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.2
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.77
MutPred		0.83		Loss of MoRF binding (P = 0.0211)
MVP		0.74
MPC		2.6
ClinPred		1.0	D
GERP RS		2.7
PromoterAI		-0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs397514499; hg19: chr19-47349359;