12-65966384-C-T

Variant names:

• chr12-65966384-C-T
• rs7970350
• NM_003483.6:c.*3092C>T

Variant summary

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

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.789
• Publications: 34 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.789 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.*3092C>T		downstream_gene	N/A	NP_003474.1	P52926-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGA2	ENST00000403681.7	TSL:1 MANE Select	c.*3092C>T		downstream_gene	N/A	ENSP00000384026.2	P52926-1
	HMGA2	ENST00000913613.1		c.*3092C>T		downstream_gene	N/A	ENSP00000583672.1

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74826 AN: 151916 Hom.: 19265 Cov.: 32

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

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: 82 AN: 142

European-Non Finnish (NFE) AF: 0.505 AC: 6051 AN: 11972

Other (OTH) AF: 0.517 AC: 858 AN: 1658

GnomAD4 genome AF: 0.492 AC: 74840 AN: 152034 Hom.: 19260 Cov.: 32 AF XY: 0.500 AC XY: 37122 AN XY: 74302

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.91
DANN	Benign	0.67
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs7970350; hg19: chr12-66360164;