rs12425829

Variant names:

• chr12-65885319-T-A
• rs12425829
• NM_003483.6:c.249+46750T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003483.6(HMGA2):​c.249+46750T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0464 in 152,282 control chromosomes in the GnomAD database, including 451 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 0.046 (451 hom., cov: 32)
• Consequence: HMGA2 NM_003483.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.308
• Publications: 2 publications found

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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• uterine corpus leiomyoma

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.246 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGA2	NM_003483.6	MANE Select	c.249+46750T>A		intron	N/A	NP_003474.1	P52926-1
	HMGA2	NM_001300919.1		c.250-29401T>A		intron	N/A	NP_001287848.1	Q1M183
	HMGA2	NM_001300918.1		c.249+46750T>A		intron	N/A	NP_001287847.1	F5H2A4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGA2	ENST00000403681.7	TSL:1 MANE Select	c.249+46750T>A		intron	N/A	ENSP00000384026.2	P52926-1
	HMGA2	ENST00000536545.5	TSL:1	c.250-29401T>A		intron	N/A	ENSP00000437621.1	F5H6H0
	HMGA2	ENST00000354636.7	TSL:1	c.250-29740T>A		intron	N/A	ENSP00000346658.3	P52926-2

Frequencies

GnomAD3 genomes AF: 0.0464 AC: 7055 AN: 152164 Hom.: 450 Cov.: 32

Gnomad AFR AF: 0.0636

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0552

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.0444

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

GnomAD4 genome AF: 0.0464 AC: 7073 AN: 152282 Hom.: 451 Cov.: 32 AF XY: 0.0527 AC XY: 3926 AN XY: 74476

African (AFR) AF: 0.0639 AC: 2655 AN: 41562

American (AMR) AF: 0.0552 AC: 843 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3472

East Asian (EAS) AF: 0.185 AC: 960 AN: 5186

South Asian (SAS) AF: 0.258 AC: 1245 AN: 4820

European-Finnish (FIN) AF: 0.0332 AC: 353 AN: 10626

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0125 AC: 847 AN: 68016

Other (OTH) AF: 0.0440 AC: 93 AN: 2116

Alfa AF: 0.0266 Hom.: 20

Bravo AF: 0.0458

Asia WGS AF: 0.221 AC: 768 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12425829; hg19: chr12-66279099;