12-65961131-G-A

Variant names:

• chr12-65961131-G-A
• rs867633
• NM_003483.6:c.283-2114G>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.283-2114G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 152,032 control chromosomes in the GnomAD database, including 14,425 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 0.42 (14425 hom., cov: 33)
• Consequence: HMGA2 NM_003483.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.54
• Publications: 8 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.834 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.283-2114G>A		intron	N/A	NP_003474.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGA2	ENST00000403681.7	TSL:1 MANE Select	c.283-2114G>A		intron	N/A	ENSP00000384026.2
	HMGA2	ENST00000539662.1	TSL:3	n.*152-2114G>A		intron	N/A	ENSP00000440919.1

Frequencies

GnomAD3 genomes AF: 0.422 AC: 64129 AN: 151912 Hom.: 14416 Cov.: 33

Gnomad AFR AF: 0.358

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.855

Gnomad SAS AF: 0.615

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.457

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

GnomAD4 genome AF: 0.422 AC: 64166 AN: 152032 Hom.: 14425 Cov.: 33 AF XY: 0.429 AC XY: 31885 AN XY: 74294

African (AFR) AF: 0.358 AC: 14865 AN: 41492

American (AMR) AF: 0.516 AC: 7882 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 1795 AN: 3466

East Asian (EAS) AF: 0.855 AC: 4425 AN: 5178

South Asian (SAS) AF: 0.615 AC: 2967 AN: 4822

European-Finnish (FIN) AF: 0.394 AC: 4148 AN: 10536

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26588 AN: 67952

Other (OTH) AF: 0.454 AC: 959 AN: 2112

Alfa AF: 0.411 Hom.: 45409

Bravo AF: 0.433

Asia WGS AF: 0.645 AC: 2238 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.011
DANN	Benign	0.54
PhyloP100		-2.5
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: rs867633; hg19: chr12-66354911;