rs62625753

Positions:

• chr3-186854237-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP4_Strong BP6_Very_Strong BS2

The ENST00000320741.7(ADIPOQ):​c.268G>A​(p.Gly90Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,613,664 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (15 hom.)
• Consequence: ADIPOQ ENST00000320741.7 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.94

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 Benign. Variant got -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.025646985).
• BP6: Variant 3-186854237-G-A is Benign according to our data. Variant chr3-186854237-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 789279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 431 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADIPOQ	NM_004797.4	c.268G>A	p.Gly90Ser	missense_variant	3/3	ENST00000320741.7	NP_004788.1
ADIPOQ-AS1	NR_046662.2	n.2016C>T		non_coding_transcript_exon_variant	2/4
ADIPOQ	NM_001177800.2	c.268G>A	p.Gly90Ser	missense_variant	4/4		NP_001171271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADIPOQ	ENST00000320741.7	c.268G>A	p.Gly90Ser	missense_variant	3/3	1	NM_004797.4	ENSP00000320709	P1
ADIPOQ	ENST00000444204.2	c.268G>A	p.Gly90Ser	missense_variant	4/4	1		ENSP00000389814	P1
ADIPOQ-AS1	ENST00000422718.1	n.1887C>T		non_coding_transcript_exon_variant	1/3	5

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152218 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00478

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00299 AC: 752 AN: 251152 Hom.: 3 AF XY: 0.00309 AC XY: 420 AN XY: 135730

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00609

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000654

Gnomad FIN exome AF: 0.000694

Gnomad NFE exome AF: 0.00482

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00320 AC: 4679 AN: 1461326 Hom.: 15 Cov.: 31 AF XY: 0.00322 AC XY: 2338 AN XY: 726886

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00567

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000835

Gnomad4 FIN exome AF: 0.000674

Gnomad4 NFE exome AF: 0.00358

Gnomad4 OTH exome AF: 0.00394

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152338 Hom.: 2 Cov.: 31 AF XY: 0.00278 AC XY: 207 AN XY: 74498

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00478

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00431 Hom.: 2

Bravo AF: 0.00301

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00302 AC: 367

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00589

EpiControl AF: 0.00616

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

ADIPOQ-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.026	T;T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.72
MVP		0.94
ClinPred		0.067	T
GERP RS		5.5
Varity_R		0.97
gMVP		0.85

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: rs62625753; hg19: chr3-186572026;