12-65939995-T-G

Variant names:

• chr12-65939995-T-G
• rs11175973
• NM_003483.6:c.250-11388T>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.250-11388T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 152,282 control chromosomes in the GnomAD database, including 86 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 0.023 (86 hom., cov: 32)
• Consequence: HMGA2 NM_003483.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.127
• Publications: 2 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0826 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.250-11388T>G		intron	N/A	NP_003474.1
	HMGA2-AS2	NR_199056.1		n.8403A>C		non_coding_transcript_exon	Exon 2 of 2
	HMGA2-AS2	NR_199057.1		n.1561A>C		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGA2	ENST00000403681.7	TSL:1 MANE Select	c.250-11388T>G		intron	N/A	ENSP00000384026.2
	HMGA2	ENST00000541363.5	TSL:1	c.250-11388T>G		intron	N/A	ENSP00000439317.1
	HMGA2	ENST00000393577.7	TSL:3	c.250-11388T>G		intron	N/A	ENSP00000377205.3

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3446 AN: 152164 Hom.: 85 Cov.: 32

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0893

Gnomad SAS AF: 0.0749

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.0249

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

GnomAD4 genome AF: 0.0227 AC: 3457 AN: 152282 Hom.: 86 Cov.: 32 AF XY: 0.0241 AC XY: 1796 AN XY: 74454

African (AFR) AF: 0.0376 AC: 1562 AN: 41554

American (AMR) AF: 0.0136 AC: 208 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.0893 AC: 463 AN: 5182

South Asian (SAS) AF: 0.0752 AC: 363 AN: 4828

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10602

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0107 AC: 727 AN: 68028

Other (OTH) AF: 0.0256 AC: 54 AN: 2112

Alfa AF: 0.00751 Hom.: 9

Bravo AF: 0.0241

Asia WGS AF: 0.0790 AC: 274 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.84
DANN	Benign	0.42
PhyloP100		-0.13
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: rs11175973; hg19: chr12-66333775;