3-57269656-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012096.3(APPL1):c.2099A>G(p.Glu700Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,613,446 control chromosomes in the GnomAD database, including 24,677 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1441 hom., cov: 32)
  • Exomes 𝑓: 0.17 (23236 hom.)
• Consequence: APPL1 NM_012096.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 8.65

Genes affected

APPL1 (HGNC:24035): (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) The protein encoded by this gene has been shown to be involved in the regulation of cell proliferation, and in the crosstalk between the adiponectin signalling and insulin signalling pathways. The encoded protein binds many other proteins, including RAB5A, DCC, AKT2, PIK3CA, adiponectin receptors, and proteins of the NuRD/MeCP1 complex. This protein is found associated with endosomal membranes, but can be released by EGF and translocated to the nucleus. [provided by RefSeq, Jul 2008]

ASB14 (HGNC:19766): (ankyrin repeat and SOCS box containing 14) The protein encoded by this gene is a member of the ankyrin repeat and SOCS box-containing (ASB) family of proteins. They contain ankyrin repeat sequence and a SOCS box domain. The SOCS box serves to couple suppressor of cytokine signalling (SOCS) proteins and their binding partners with the elongin B and C complex, possibly targeting them for degradation. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Dec 2008]

LOC105377102 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015658736).
• BP6: Variant 3-57269656-A-G is Benign according to our data. Variant chr3-57269656-A-G is described in ClinVar as [Benign]. Clinvar id is 1168989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APPL1	NM_012096.3	c.2099A>G	p.Glu700Gly	missense_variant	22/22	ENST00000288266.8
ASB14	NM_001142733.3	c.*23-38T>C		intron_variant		ENST00000487349.6
LOC105377102	NR_135535.1	n.91A>G		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APPL1	ENST00000288266.8	c.2099A>G	p.Glu700Gly	missense_variant	22/22	1	NM_012096.3	P1
ASB14	ENST00000487349.6	c.*23-38T>C		intron_variant		1	NM_001142733.3	P1
APPL1	ENST00000650354.1	c.2099A>G	p.Glu700Gly	missense_variant, NMD_transcript_variant	22/24

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17989 AN: 152036 Hom.: 1441 Cov.: 32

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.0355

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.108

GnomAD3 exomes AF: 0.129 AC: 32481 AN: 251348 Hom.: 2721 AF XY: 0.132 AC XY: 17991 AN XY: 135840

Gnomad AFR exome AF: 0.0295

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.0402

Gnomad EAS exome AF: 0.000815

Gnomad SAS exome AF: 0.115

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.169 AC: 247627 AN: 1461292 Hom.: 23236 Cov.: 32 AF XY: 0.168 AC XY: 121800 AN XY: 726954

Gnomad4 AFR exome AF: 0.0247

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.0414

Gnomad4 EAS exome AF: 0.000706

Gnomad4 SAS exome AF: 0.118

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.191

Gnomad4 OTH exome AF: 0.146

GnomAD4 genome AF: 0.118 AC: 17984 AN: 152154 Hom.: 1441 Cov.: 32 AF XY: 0.117 AC XY: 8690 AN XY: 74376

Gnomad4 AFR AF: 0.0327

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.0355

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.110

Gnomad4 FIN AF: 0.178

Gnomad4 NFE AF: 0.177

Gnomad4 OTH AF: 0.107

Alfa AF: 0.156 Hom.: 4755

Bravo AF: 0.109

TwinsUK AF: 0.186 AC: 690

ALSPAC AF: 0.201 AC: 775

ESP6500AA AF: 0.0433 AC: 191

ESP6500EA AF: 0.171 AC: 1470

ExAC AF: 0.130 AC: 15752

Asia WGS AF: 0.0480 AC: 169 AN: 3478

EpiCase AF: 0.165

EpiControl AF: 0.161

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	23
Dann	Benign	0.96
DEOGEN2	Benign	0.060	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.000013	P;P;P
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.14
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.18	T
Polyphen		0.46	P
Vest4		0.17
MPC		0.26
ClinPred		0.052	T
GERP RS		5.7
Varity_R		0.14
gMVP		0.12

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: rs11544593; hg19: chr3-57303684; COSMIC: COSV55699524; COSMIC: COSV55699524;