3-57268494-A-G

Position:

• chr3-57268494-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_012096.3(APPL1):​c.1983+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,584,180 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (2 hom.)
• Consequence: APPL1 NM_012096.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003680
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.09

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-57268494-A-G is Benign according to our data. Variant chr3-57268494-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1551890.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASB14	NM_001142733.3	c.*1147T>C		3_prime_UTR_variant	11/11	ENST00000487349.6	NP_001136205.2
APPL1	NM_012096.3	c.1983+7A>G		splice_region_variant, intron_variant		ENST00000288266.8	NP_036228.1
ASB14	NM_130387.5	c.*1147T>C		3_prime_UTR_variant	4/4		NP_569058.1
APPL1	XM_011533583.4	c.1932+7A>G		splice_region_variant, intron_variant			XP_011531885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASB14	ENST00000487349.6	c.*1147T>C		3_prime_UTR_variant	11/11	1	NM_001142733.3	ENSP00000419199	P1
APPL1	ENST00000288266.8	c.1983+7A>G		splice_region_variant, intron_variant		1	NM_012096.3	ENSP00000288266	P1
APPL1	ENST00000650354.1	c.1983+7A>G		splice_region_variant, intron_variant, NMD_transcript_variant				ENSP00000498115

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152246 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000179 AC: 41 AN: 229594 Hom.: 0 AF XY: 0.000136 AC XY: 17 AN XY: 124816

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000619

Gnomad FIN exome AF: 0.0000498

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.000366

GnomAD4 exome AF: 0.000103 AC: 148 AN: 1431816 Hom.: 2 Cov.: 30 AF XY: 0.000119 AC XY: 85 AN XY: 712136

Gnomad4 AFR exome AF: 0.0000629

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000406

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000640

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000681

Gnomad4 OTH exome AF: 0.000254

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152364 Hom.: 1 Cov.: 32 AF XY: 0.0000805 AC XY: 6 AN XY: 74518

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.0000822 Hom.: 0

Bravo AF: 0.0000604

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.5
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.050		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: rs368162592; hg19: chr3-57302522;