rs1042725

Variant names:

• chr12-65964567-C-T
• rs1042725
• NM_003483.6:c.*1275C>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.*1275C>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 0.508 in 215,618 control chromosomes in the GnomAD database, including 29,032 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 (19233 hom., cov: 31)
  • Exomes 𝑓: 0.54 (9799 hom.)
• Consequence: HMGA2 NM_003483.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.508
• Publications: 121 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: 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=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGA2	NM_003483.6	c.*1275C>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000403681.7	NP_003474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGA2	ENST00000403681.7	c.*1275C>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_003483.6	ENSP00000384026.2

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74760 AN: 151686 Hom.: 19238 Cov.: 31

Gnomad AFR AF: 0.384

Gnomad AMI AF: 0.529

Gnomad AMR AF: 0.588

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.811

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.487

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.528

GnomAD4 exome AF: 0.543 AC: 34681 AN: 63814 Hom.: 9799 Cov.: 0 AF XY: 0.544 AC XY: 16165 AN XY: 29720

African (AFR) AF: 0.391 AC: 1166 AN: 2984

American (AMR) AF: 0.593 AC: 1111 AN: 1874

Ashkenazi Jewish (ASJ) AF: 0.644 AC: 2611 AN: 4054

East Asian (EAS) AF: 0.729 AC: 6724 AN: 9226

South Asian (SAS) AF: 0.713 AC: 385 AN: 540

European-Finnish (FIN) AF: 0.502 AC: 236 AN: 470

Middle Eastern (MID) AF: 0.608 AC: 237 AN: 390

European-Non Finnish (NFE) AF: 0.499 AC: 19420 AN: 38920

Other (OTH) AF: 0.521 AC: 2791 AN: 5356

GnomAD4 genome AF: 0.493 AC: 74774 AN: 151804 Hom.: 19233 Cov.: 31 AF XY: 0.500 AC XY: 37101 AN XY: 74192

African (AFR) AF: 0.384 AC: 15874 AN: 41388

American (AMR) AF: 0.587 AC: 8962 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 2279 AN: 3470

East Asian (EAS) AF: 0.810 AC: 4174 AN: 5150

South Asian (SAS) AF: 0.676 AC: 3259 AN: 4818

European-Finnish (FIN) AF: 0.487 AC: 5127 AN: 10518

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.491 AC: 33348 AN: 67886

Other (OTH) AF: 0.524 AC: 1106 AN: 2110

Alfa AF: 0.507 Hom.: 81469

Bravo AF: 0.499

Asia WGS AF: 0.680 AC: 2360 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.2
DANN	Benign	0.46
PhyloP100		0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1042725; hg19: chr12-66358347; COSMIC: COSV67804157; COSMIC: COSV67804157;