NM_003483.6:c.250-6961G>T

Variant names:

• chr12-65944422-G-T
• rs17101923
• NM_003483.6:c.250-6961G>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.250-6961G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 152,008 control chromosomes in the GnomAD database, including 5,210 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 0.25 (5210 hom., cov: 32)
• Consequence: HMGA2 NM_003483.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.435
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGA2	NM_003483.6	c.250-6961G>T		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.250-6961G>T		intron_variant	Intron 3 of 4	1	NM_003483.6	ENSP00000384026.2

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38593 AN: 151890 Hom.: 5193 Cov.: 32

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.275

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

GnomAD4 genome AF: 0.254 AC: 38648 AN: 152008 Hom.: 5210 Cov.: 32 AF XY: 0.257 AC XY: 19097 AN XY: 74284

African (AFR) AF: 0.301 AC: 12472 AN: 41438

American (AMR) AF: 0.231 AC: 3529 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 984 AN: 3470

East Asian (EAS) AF: 0.147 AC: 762 AN: 5168

South Asian (SAS) AF: 0.400 AC: 1925 AN: 4814

European-Finnish (FIN) AF: 0.246 AC: 2591 AN: 10548

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15475 AN: 67986

Other (OTH) AF: 0.273 AC: 577 AN: 2110

Alfa AF: 0.234 Hom.: 6988

Bravo AF: 0.255

Asia WGS AF: 0.259 AC: 900 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.4
DANN	Benign	0.42
PhyloP100		0.43
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: rs17101923; hg19: chr12-66338202;