Genetic Variant HMGA2:c.249+28575A>G (chr12-65867144-A-G) – 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.249+28575A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.638 in 152,142 control chromosomes in the GnomAD database, including 37,750 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 0.64 ( 37750 hom., cov: 32)

Consequence

HMGA2
NM_003483.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0770

Publications

8 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 links:

HMGA2-AS1 (HGNC:53973): (HMGA2 antisense RNA 1)

HMGA2-AS1 links:

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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=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003483.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HMGA2	NM_003483.6	MANE Select	c.249+28575A>G	intron	N/A	NP_003474.1	P52926-1
HMGA2	NM_001300919.1		c.249+28575A>G	intron	N/A	NP_001287848.1	Q1M183
HMGA2	NM_001300918.1		c.249+28575A>G	intron	N/A	NP_001287847.1	F5H2A4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HMGA2	ENST00000403681.7	TSL:1 MANE Select	c.249+28575A>G	intron	N/A	ENSP00000384026.2	P52926-1
HMGA2	ENST00000536545.5	TSL:1	c.249+28575A>G	intron	N/A	ENSP00000437621.1	F5H6H0
HMGA2	ENST00000354636.7	TSL:1	c.249+28575A>G	intron	N/A	ENSP00000346658.3	P52926-2

Frequencies

GnomAD3 genomes

AF:

0.639

AC:

97129

AN:

152024

Hom.:

37746

Cov.:

show subpopulations

Gnomad AFR

AF:

0.172

Gnomad AMI

AF:

0.916

Gnomad AMR

AF:

0.752

Gnomad ASJ

AF:

0.719

Gnomad EAS

AF:

0.668

Gnomad SAS

AF:

0.570

Gnomad FIN

AF:

0.863

Gnomad MID

AF:

0.677

Gnomad NFE

AF:

0.857

Gnomad OTH

AF:

0.656

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.638

AC:

97126

AN:

152142

Hom.:

37750

Cov.:

AF XY:

0.638

AC XY:

47444

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.172

AC:

7120

AN:

41502

American (AMR)

AF:

0.753

AC:

11497

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.719

AC:

2492

AN:

3468

East Asian (EAS)

AF:

0.667

AC:

3448

AN:

5166

South Asian (SAS)

AF:

0.571

AC:

2753

AN:

4820

European-Finnish (FIN)

AF:

0.863

AC:

9150

AN:

10598

Middle Eastern (MID)

AF:

0.677

AC:

199

AN:

294

European-Non Finnish (NFE)

AF:

0.857

AC:

58262

AN:

67998

Other (OTH)

AF:

0.651

AC:

1370

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1103

2206

3310

4413

5516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

726

1452

2178

2904

3630

<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:

0.777

Hom.:

61371

Bravo

AF:

0.613

Asia WGS

AF:

0.551

AC:

1920

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.3

(source)

DANN

Benign

0.47

PhyloP100

0.077

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over