12-65966288-C-T

Variant names:

• chr12-65966288-C-T
• rs11175982
• NM_003483.6:c.*2996C>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.*2996C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 185,090 control chromosomes in the GnomAD database, including 6,450 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 0.21 (4430 hom., cov: 32)
  • Exomes 𝑓: 0.30 (2020 hom.)
• Consequence: HMGA2 NM_003483.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 10 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=-0.67).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.731 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.*2996C>T		3_prime_UTR	Exon 5 of 5	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.*2996C>T		3_prime_UTR	Exon 5 of 5	ENSP00000384026.2	P52926-1
	HMGA2	ENST00000913613.1		c.*2996C>T		downstream_gene	N/A	ENSP00000583672.1

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31698 AN: 151946 Hom.: 4433 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.217

GnomAD4 exome AF: 0.295 AC: 9747 AN: 33026 Hom.: 2020 Cov.: 0 AF XY: 0.287 AC XY: 4419 AN XY: 15388

African (AFR) AF: 0.155 AC: 184 AN: 1188

American (AMR) AF: 0.339 AC: 265 AN: 782

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 587 AN: 2066

East Asian (EAS) AF: 0.676 AC: 4221 AN: 6244

South Asian (SAS) AF: 0.331 AC: 92 AN: 278

European-Finnish (FIN) AF: 0.170 AC: 76 AN: 446

Middle Eastern (MID) AF: 0.231 AC: 49 AN: 212

European-Non Finnish (NFE) AF: 0.192 AC: 3675 AN: 19134

Other (OTH) AF: 0.223 AC: 598 AN: 2676

GnomAD4 genome AF: 0.208 AC: 31697 AN: 152064 Hom.: 4430 Cov.: 32 AF XY: 0.213 AC XY: 15849 AN XY: 74352

African (AFR) AF: 0.144 AC: 5957 AN: 41472

American (AMR) AF: 0.312 AC: 4754 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 917 AN: 3468

East Asian (EAS) AF: 0.750 AC: 3875 AN: 5164

South Asian (SAS) AF: 0.293 AC: 1412 AN: 4814

European-Finnish (FIN) AF: 0.158 AC: 1674 AN: 10598

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.183 AC: 12425 AN: 67976

Other (OTH) AF: 0.216 AC: 457 AN: 2112

Alfa AF: 0.197 Hom.: 2262

Bravo AF: 0.222

Asia WGS AF: 0.461 AC: 1599 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.0
DANN	Benign	0.72
PhyloP100		1.2
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: rs11175982; hg19: chr12-66360068;