Genetic Variant NM_000025.3:c.1205+319_1205+320delTT (chr8-37964944-TAA-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000025.3(ADRB3):c.1205+319_1205+320delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 241,246 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 31)

Exomes 𝑓: 0.010 ( 0 hom. )

Consequence

ADRB3
NM_000025.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.61

Publications

0 publications found

Variant links:

Genes affected

ADRB3 (HGNC:288): (adrenoceptor beta 3) The protein encoded by this gene belongs to the family of beta adrenergic receptors, which mediate catecholamine-induced activation of adenylate cyclase through the action of G proteins. This receptor is located mainly in the adipose tissue and is involved in the regulation of lipolysis and thermogenesis. Obesity and bodyweight-related disorders are correlated with certain polymorphisms in three subtypes of beta-adrenoceptor, among them, the ADRB3 gene.[provided by RefSeq, Oct 2019]

ADRB3 links:

ENSG00000285880 (HGNC:):

ENSG00000285880 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Variant has high frequency in the MID (0.00946) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADRB3	NM_000025.3 link	c.1205+319_1205+320delTT		intron_variant	Intron 1 of 1	ENST00000345060.5	NP_000016.1	P13945A8KAG8

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADRB3	ENST00000345060.5 link	c.1205+319_1205+320delTT	intron_variant	Intron 1 of 1	1	NM_000025.3	ENSP00000343782.3	P13945
ENSG00000285880	ENST00000647937.1 link	c.689+319_689+320delTT	intron_variant	Intron 1 of 1			ENSP00000497740.1	A0A3B3IT50
ADRB3	ENST00000520341.2 link	n.28_29delTT	downstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.00000693

AC:

AN:

144392

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0101

AC:

982

AN:

96792

Hom.:

AF XY:

0.0103

AC XY:

500

AN XY:

48406

show subpopulations

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

African (AFR)

AF:

0.0117

AC:

AN:

2996

American (AMR)

AF:

0.0114

AC:

AN:

2554

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3640

East Asian (EAS)

AF:

0.00933

AC:

AN:

7292

South Asian (SAS)

AF:

0.00882

AC:

AN:

2382

European-Finnish (FIN)

AF:

0.00958

AC:

AN:

5532

Middle Eastern (MID)

AF:

0.0125

AC:

AN:

560

European-Non Finnish (NFE)

AF:

0.0101

AC:

657

AN:

65036

Other (OTH)

AF:

0.0101

AC:

AN:

6800

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.254

Heterozygous variant carriers

122

244

366

488

610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000692

AC:

AN:

144454

Hom.:

Cov.:

AF XY:

0.0000143

AC XY:

AN XY:

70164

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

39378

American (AMR)

AF:

0.00

AC:

AN:

14610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3360

East Asian (EAS)

AF:

0.00

AC:

AN:

4920

South Asian (SAS)

AF:

0.00

AC:

AN:

4532

European-Finnish (FIN)

AF:

0.000113

AC:

AN:

8852

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65626

Other (OTH)

AF:

0.00

AC:

AN:

2010

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

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

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NM_000025.3:c.1205+319_1205+320delTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over