NM_015999.6:c.1000-4A>G

Variant names:

• chr1-202941705-T-C
• rs1303306359
• NM_015999.6:c.1000-4A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_015999.6(ADIPOR1):​c.1000-4A>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 0.00000137 in 1,455,512 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADIPOR1 NM_015999.6 splice_region, intron
• Scores: Splicing: ADA: 0.00008145
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.48
• Publications: 0 publications found

Genes affected

ADIPOR1 (HGNC:24040): (adiponectin receptor 1) This gene encodes a protein which acts as a receptor for adiponectin, a hormone secreted by adipocytes which regulates fatty acid catabolism and glucose levels. Binding of adiponectin to the encoded protein results in activation of an AMP-activated kinase signaling pathway which affects levels of fatty acid oxidation and insulin sensitivity. A pseudogene of this gene is located on chromosome 14. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2014]

ADIPOR1 Gene-Disease associations (from GenCC):

• retinitis pigmentosa

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-202941705-T-C is Benign according to our data. Variant chr1-202941705-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2095571.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015999.6. 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
	ADIPOR1	NM_015999.6	MANE Select	c.1000-4A>G		splice_region intron	N/A	NP_057083.2
	ADIPOR1	NM_001290553.2		c.1000-4A>G		splice_region intron	N/A	NP_001277482.1	Q96A54
	ADIPOR1	NM_001290557.1		c.1000-4A>G		splice_region intron	N/A	NP_001277486.1	Q96A54

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADIPOR1	ENST00000340990.10	TSL:1 MANE Select	c.1000-4A>G		splice_region intron	N/A	ENSP00000341785.5	Q96A54
	ADIPOR1	ENST00000367254.7	TSL:1	c.*215-4A>G		splice_region intron	N/A	ENSP00000356223.3	F8W782
	ADIPOR1	ENST00000855702.1		c.1000-4A>G		splice_region intron	N/A	ENSP00000525761.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455512 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724064

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32786

American (AMR) AF: 0.00 AC: 0 AN: 42738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25810

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 84858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110482

Other (OTH) AF: 0.00 AC: 0 AN: 60080

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.4
DANN	Benign	0.53
PhyloP100		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000081
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs1303306359; hg19: chr1-202910833;