12-65933163-A-G

Variant names:

• chr12-65933163-A-G
• rs1480474
• NM_003483.6:c.250-18220A>G

Variant summary

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

The NM_003483.6(HMGA2):​c.250-18220A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 151,724 control chromosomes in the GnomAD database, including 17,290 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 0.46 (17290 hom., cov: 31)
• Consequence: HMGA2 NM_003483.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.318
• Publications: 14 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)

HMGA2-AS2 (HGNC:58191):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.875 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGA2	NM_003483.6	MANE Select	c.250-18220A>G		intron	N/A	NP_003474.1
	HMGA2	NM_001300918.1		c.250-18220A>G		intron	N/A	NP_001287847.1
	HMGA2-AS2	NR_199059.1		n.*155T>C		downstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGA2	ENST00000403681.7	TSL:1 MANE Select	c.250-18220A>G		intron	N/A	ENSP00000384026.2
	HMGA2	ENST00000541363.5	TSL:1	c.250-18220A>G		intron	N/A	ENSP00000439317.1
	HMGA2	ENST00000393577.7	TSL:3	c.250-18220A>G		intron	N/A	ENSP00000377205.3

Frequencies

GnomAD3 genomes AF: 0.464 AC: 70399 AN: 151606 Hom.: 17269 Cov.: 31

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.896

Gnomad SAS AF: 0.692

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.414

Gnomad OTH AF: 0.500

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

GnomAD4 genome AF: 0.464 AC: 70457 AN: 151724 Hom.: 17290 Cov.: 31 AF XY: 0.472 AC XY: 35006 AN XY: 74124

African (AFR) AF: 0.443 AC: 18300 AN: 41328

American (AMR) AF: 0.546 AC: 8314 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1952 AN: 3470

East Asian (EAS) AF: 0.896 AC: 4626 AN: 5162

South Asian (SAS) AF: 0.692 AC: 3324 AN: 4802

European-Finnish (FIN) AF: 0.401 AC: 4212 AN: 10516

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.414 AC: 28124 AN: 67916

Other (OTH) AF: 0.498 AC: 1044 AN: 2098

Alfa AF: 0.449 Hom.: 12799

Bravo AF: 0.479

Asia WGS AF: 0.723 AC: 2511 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.7
DANN	Benign	0.59
PhyloP100		0.32
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: rs1480474; hg19: chr12-66326943;