Genetic Variant HMGA2:c.*3092C>T (chr12-65966384-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003483.6(HMGA2):c.*3092C>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 173,088 control chromosomes in the GnomAD database, including 22,691 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.49 ( 19260 hom., cov: 32)

Exomes 𝑓: 0.56 ( 3431 hom. )

Consequence

HMGA2
NM_003483.6 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.789

Publications

34 publications found

Variant links:

Genes affected

HMGA2 (HGNC:5009): (high mobility group AT-hook 2) This gene encodes a protein that belongs to the non-histone chromosomal high mobility group (HMG) protein family. HMG proteins function as architectural factors and are essential components of the enhancesome. This protein contains structural DNA-binding domains and may act as a transcriptional regulating factor. Identification of the deletion, amplification, and rearrangement of this gene that are associated with myxoid liposarcoma suggests a role in adipogenesis and mesenchymal differentiation. A gene knock out study of the mouse counterpart demonstrated that this gene is involved in diet-induced obesity. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

HMGA2 Gene-Disease associations (from GenCC):

Silver-Russell syndrome 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
uterine corpus leiomyoma
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

HMGA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGA2	NM_003483.6 link	c.*3092C>T		downstream_gene_variant		ENST00000403681.7	NP_003474.1	P52926-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGA2	ENST00000403681.7 link	c.*3092C>T		downstream_gene_variant		1	NM_003483.6	ENSP00000384026.2		P52926-1

Frequencies

GnomAD3 genomes

AF:

0.493

AC:

74826

AN:

151916

Hom.:

19265

Cov.:

show subpopulations

Gnomad AFR

AF:

0.384

Gnomad AMI

AF:

0.529

Gnomad AMR

AF:

0.588

Gnomad ASJ

AF:

0.655

Gnomad EAS

AF:

0.810

Gnomad SAS

AF:

0.676

Gnomad FIN

AF:

0.486

Gnomad MID

AF:

0.570

Gnomad NFE

AF:

0.491

Gnomad OTH

AF:

0.527

GnomAD4 exome

AF:

0.560

AC:

11783

AN:

21054

Hom.:

3431

AF XY:

0.561

AC XY:

5492

AN XY:

9788

show subpopulations

African (AFR)

AF:

0.391

AC:

266

AN:

680

American (AMR)

AF:

0.557

AC:

244

AN:

438

Ashkenazi Jewish (ASJ)

AF:

0.640

AC:

853

AN:

1332

East Asian (EAS)

AF:

0.731

AC:

3104

AN:

4248

South Asian (SAS)

AF:

0.713

AC:

114

AN:

160

European-Finnish (FIN)

AF:

0.498

AC:

211

AN:

424

Middle Eastern (MID)

AF:

0.577

AC:

AN:

142

European-Non Finnish (NFE)

AF:

0.505

AC:

6051

AN:

11972

Other (OTH)

AF:

0.517

AC:

858

AN:

1658

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

234

467

701

934

1168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.492

AC:

74840

AN:

152034

Hom.:

19260

Cov.:

AF XY:

0.500

AC XY:

37122

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.384

AC:

15899

AN:

41454

American (AMR)

AF:

0.587

AC:

8970

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.655

AC:

2273

AN:

3470

East Asian (EAS)

AF:

0.809

AC:

4183

AN:

5170

South Asian (SAS)

AF:

0.676

AC:

3258

AN:

4820

European-Finnish (FIN)

AF:

0.486

AC:

5140

AN:

10566

Middle Eastern (MID)

AF:

0.558

AC:

164

AN:

294

European-Non Finnish (NFE)

AF:

0.491

AC:

33368

AN:

67968

Other (OTH)

AF:

0.524

AC:

1104

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1881

3761

5642

7522

9403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

674

1348

2022

2696

3370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.490

Hom.:

30822

Bravo

AF:

0.499

Asia WGS

AF:

0.679

AC:

2358

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.91

(source)

DANN

Benign

0.67

PhyloP100

-0.79

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over