12-65966494-T-C

Variant names:

• chr12-65966494-T-C
• rs10506474
• NM_003483.6:c.*3202T>C

Variant summary

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

The NM_003483.6(HMGA2):​c.*3202T>C variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 152,220 control chromosomes in the GnomAD database, including 3,509 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 0.17 (3509 hom., cov: 32)
• Consequence: HMGA2 NM_003483.6 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.87
• Publications: 4 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGA2	NM_003483.6	c.*3202T>C		downstream_gene_variant		ENST00000403681.7	NP_003474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGA2	ENST00000403681.7	c.*3202T>C		downstream_gene_variant		1	NM_003483.6	ENSP00000384026.2

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26145 AN: 152102 Hom.: 3514 Cov.: 32

Gnomad AFR AF: 0.0404

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.194

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

GnomAD4 genome AF: 0.172 AC: 26134 AN: 152220 Hom.: 3509 Cov.: 32 AF XY: 0.176 AC XY: 13065 AN XY: 74428

African (AFR) AF: 0.0403 AC: 1676 AN: 41566

American (AMR) AF: 0.289 AC: 4411 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 913 AN: 3468

East Asian (EAS) AF: 0.679 AC: 3503 AN: 5158

South Asian (SAS) AF: 0.224 AC: 1081 AN: 4828

European-Finnish (FIN) AF: 0.144 AC: 1530 AN: 10590

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12387 AN: 68022

Other (OTH) AF: 0.193 AC: 409 AN: 2114

Alfa AF: 0.199 Hom.: 1367

Bravo AF: 0.183

Asia WGS AF: 0.376 AC: 1304 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.39
DANN	Benign	0.36
PhyloP100		-1.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10506474; hg19: chr12-66360274;