rs1480468

Variant names:

• chr12-65948337-G-A
• rs1480468
• NM_003483.6:c.250-3046G>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.250-3046G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0968 in 152,144 control chromosomes in the GnomAD database, including 768 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 0.097 (768 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HMGA2 NM_003483.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.499
• Publications: 5 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)

ENSG00000256083 (HGNC:58191):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGA2	NM_003483.6	c.250-3046G>A		intron_variant	Intron 3 of 4	ENST00000403681.7	NP_003474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGA2	ENST00000403681.7	c.250-3046G>A		intron_variant	Intron 3 of 4	1	NM_003483.6	ENSP00000384026.2

Frequencies

GnomAD3 genomes AF: 0.0968 AC: 14720 AN: 152026 Hom.: 770 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0901

Gnomad AMR AF: 0.0849

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0578

Gnomad FIN AF: 0.0874

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0908

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0968 AC: 14724 AN: 152144 Hom.: 768 Cov.: 32 AF XY: 0.0950 AC XY: 7067 AN XY: 74398

African (AFR) AF: 0.109 AC: 4515 AN: 41494

American (AMR) AF: 0.0847 AC: 1293 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 473 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0572 AC: 276 AN: 4822

European-Finnish (FIN) AF: 0.0874 AC: 925 AN: 10586

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6938 AN: 68006

Other (OTH) AF: 0.0898 AC: 189 AN: 2104

Alfa AF: 0.101 Hom.: 1449

Bravo AF: 0.0969

Asia WGS AF: 0.0450 AC: 157 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.16
DANN	Benign	0.70
PhyloP100		-0.50
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: rs1480468; hg19: chr12-66342117;