3-57260057-C-G

Variant names:

• chr3-57260057-C-G
• rs10510791
• NM_012096.3:c.1658+38C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012096.3(APPL1):​c.1658+38C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,605,404 control chromosomes in the GnomAD database, including 142,145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (12600 hom., cov: 32)
  • Exomes 𝑓: 0.41 (129545 hom.)
• Consequence: APPL1 NM_012096.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.497
• Publications: 13 publications found

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]

APPL1 Gene-Disease associations (from GenCC):

• maturity-onset diabetes of the young type 14

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• monogenic diabetes

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-57260057-C-G is Benign according to our data. Variant chr3-57260057-C-G is described in ClinVar as Benign. ClinVar VariationId is 1257896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APPL1	NM_012096.3	c.1658+38C>G		intron_variant	Intron 17 of 21	ENST00000288266.8	NP_036228.1
APPL1	XM_011533583.4	c.1607+38C>G		intron_variant	Intron 18 of 22		XP_011531885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APPL1	ENST00000288266.8	c.1658+38C>G		intron_variant	Intron 17 of 21	1	NM_012096.3	ENSP00000288266.3

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57586 AN: 151880 Hom.: 12579 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.847

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.386

GnomAD2 exomes AF: 0.467 AC: 112797 AN: 241728 AF XY: 0.463

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.624

Gnomad ASJ exome AF: 0.479

Gnomad EAS exome AF: 0.853

Gnomad FIN exome AF: 0.488

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.440

GnomAD4 exome AF: 0.410 AC: 596146 AN: 1453406 Hom.: 129545 Cov.: 34 AF XY: 0.412 AC XY: 298043 AN XY: 722776

African (AFR) AF: 0.179 AC: 5910 AN: 33014

American (AMR) AF: 0.607 AC: 25684 AN: 42282

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 12341 AN: 25982

East Asian (EAS) AF: 0.858 AC: 33938 AN: 39548

South Asian (SAS) AF: 0.467 AC: 39351 AN: 84234

European-Finnish (FIN) AF: 0.484 AC: 25769 AN: 53296

Middle Eastern (MID) AF: 0.453 AC: 2605 AN: 5756

European-Non Finnish (NFE) AF: 0.383 AC: 425262 AN: 1109212

Other (OTH) AF: 0.421 AC: 25286 AN: 60082

GnomAD4 genome AF: 0.379 AC: 57623 AN: 151998 Hom.: 12600 Cov.: 32 AF XY: 0.389 AC XY: 28941 AN XY: 74308

African (AFR) AF: 0.188 AC: 7820 AN: 41492

American (AMR) AF: 0.528 AC: 8074 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1656 AN: 3468

East Asian (EAS) AF: 0.848 AC: 4382 AN: 5168

South Asian (SAS) AF: 0.500 AC: 2405 AN: 4814

European-Finnish (FIN) AF: 0.490 AC: 5159 AN: 10536

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.393 AC: 26690 AN: 67922

Other (OTH) AF: 0.392 AC: 828 AN: 2110

Alfa AF: 0.336 Hom.: 1664

Bravo AF: 0.374

Asia WGS AF: 0.643 AC: 2233 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.43
DANN	Benign	0.53
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism (auto)

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: rs10510791; hg19: chr3-57294085;