3-186853191-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BP4 BS2

The NM_004797.4(ADIPOQ):c.133G>C(p.Gly45Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,613,896 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (3 hom.)
• Consequence: ADIPOQ NM_004797.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.97

Genes affected

ADIPOQ (HGNC:13633): (adiponectin, C1Q and collagen domain containing) This gene is expressed in adipose tissue exclusively. It encodes a protein with similarity to collagens X and VIII and complement factor C1q. The encoded protein circulates in the plasma and is involved with metabolic and hormonal processes. Mutations in this gene are associated with adiponectin deficiency. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Apr 2010]

ADIPOQ-AS1 (HGNC:40648): (ADIPOQ antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 12: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.31399632).
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADIPOQ	NM_004797.4	c.133G>C	p.Gly45Arg	missense_variant	2/3	ENST00000320741.7
ADIPOQ-AS1	NR_046662.2	n.2267C>G		non_coding_transcript_exon_variant	4/4
ADIPOQ	NM_001177800.2	c.133G>C	p.Gly45Arg	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADIPOQ	ENST00000320741.7	c.133G>C	p.Gly45Arg	missense_variant	2/3	1	NM_004797.4	P1
ADIPOQ	ENST00000444204.2	c.133G>C	p.Gly45Arg	missense_variant	3/4	1		P1
ADIPOQ-AS1	ENST00000422718.1	n.2138C>G		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000771 AC: 193 AN: 250432 Hom.: 3 AF XY: 0.000568 AC XY: 77 AN XY: 135502

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00560

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000137 AC: 200 AN: 1461666 Hom.: 3 Cov.: 32 AF XY: 0.000105 AC XY: 76 AN XY: 727154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00443

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74370

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000252 Hom.: 0

Bravo AF: 0.000204

ExAC AF: 0.000675 AC: 82

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 24, 2021

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in family-specific linkage studies with childhood obesity in published literature, but additional information was not available (Bowden et al., 2010; Sabo et al., 2017); This variant is associated with the following publications: (PMID: 23102667, 28508493, 20688759, 26306152) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.90		Gain of solvent accessibility (P = 0.0042);Gain of solvent accessibility (P = 0.0042);
MVP		0.99
ClinPred		0.45	T
GERP RS		5.2
Varity_R		0.96
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs200573126; hg19: chr3-186570980;