rs17366743

chr3-186854300-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004797.4(ADIPOQ):c.331T>C(p.Tyr111His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 1,614,206 control chromosomes in the GnomAD database, including 727 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.020 (50 hom., cov: 31)
  • Exomes 𝑓: 0.028 (677 hom.)
• Consequence: ADIPOQ NM_004797.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.271

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059143007).
• BP6: Variant 3-186854300-T-C is Benign according to our data. Variant chr3-186854300-T-C is described in ClinVar as [Benign]. Clinvar id is 3042029.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0205 (3118/152328) while in subpopulation NFE AF= 0.0297 (2019/68024). AF 95% confidence interval is 0.0286. There are 50 homozygotes in gnomad4. There are 1518 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 3118 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADIPOQ	NM_004797.4	c.331T>C	p.Tyr111His	missense_variant	3/3	ENST00000320741.7
ADIPOQ-AS1	NR_046662.2	n.1953A>G		non_coding_transcript_exon_variant	2/4
ADIPOQ	NM_001177800.2	c.331T>C	p.Tyr111His	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADIPOQ	ENST00000320741.7	c.331T>C	p.Tyr111His	missense_variant	3/3	1	NM_004797.4	P1
ADIPOQ	ENST00000444204.2	c.331T>C	p.Tyr111His	missense_variant	4/4	1		P1
ADIPOQ-AS1	ENST00000422718.1	n.1824A>G		non_coding_transcript_exon_variant	1/3	5

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3118 AN: 152210 Hom.: 49 Cov.: 31

Gnomad AFR AF: 0.00605

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00932

Gnomad FIN AF: 0.0387

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0297

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0219 AC: 5516 AN: 251458 Hom.: 87 AF XY: 0.0227 AC XY: 3086 AN XY: 135896

Gnomad AFR exome AF: 0.00714

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.0339

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0126

Gnomad FIN exome AF: 0.0387

Gnomad NFE exome AF: 0.0291

Gnomad OTH exome AF: 0.0274

GnomAD4 exome AF: 0.0285 AC: 41648 AN: 1461878 Hom.: 677 Cov.: 31 AF XY: 0.0280 AC XY: 20361 AN XY: 727236

Gnomad4 AFR exome AF: 0.00430

Gnomad4 AMR exome AF: 0.0107

Gnomad4 ASJ exome AF: 0.0325

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0127

Gnomad4 FIN exome AF: 0.0369

Gnomad4 NFE exome AF: 0.0319

Gnomad4 OTH exome AF: 0.0254

GnomAD4 genome AF: 0.0205 AC: 3118 AN: 152328 Hom.: 50 Cov.: 31 AF XY: 0.0204 AC XY: 1518 AN XY: 74492

Gnomad4 AFR AF: 0.00604

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.0372

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.00974

Gnomad4 FIN AF: 0.0387

Gnomad4 NFE AF: 0.0297

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0278 Hom.: 135

Bravo AF: 0.0185

TwinsUK AF: 0.0316 AC: 117

ALSPAC AF: 0.0350 AC: 135

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.0320 AC: 275

ExAC AF: 0.0212 AC: 2569

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.0278

EpiControl AF: 0.0285

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ADIPOQ-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2019

This variant is classified as 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	Benign	0.12
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	14
Dann	Benign	0.92
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.44	N
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.075
Sift	Benign	0.51	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.0060	B;B
Vest4		0.032
ClinPred		0.020	T
GERP RS		3.1
Varity_R		0.20
gMVP		0.46

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: rs17366743; hg19: chr3-186572089; COSMIC: COSV99067039;