12-65952348-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000541363.5(HMGA2):c.*915T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00819 in 1,533,102 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0080 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (52 hom.)
• Consequence: HMGA2 ENST00000541363.5 3_prime_UTR
• Scores: Splicing: ADA: 0.00006732
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.300

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-65952348-T-C is Benign according to our data. Variant chr12-65952348-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2578687.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 1221 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGA2	NM_003483.6	c.282+933T>C		intron_variant		ENST00000403681.7
HMGA2	NM_001300918.1	c.283-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGA2	ENST00000541363.5	c.*915T>C		3_prime_UTR_variant	4/4	1
HMGA2	ENST00000403681.7	c.282+933T>C		intron_variant		1	NM_003483.6	P1
HMGA2	ENST00000393577.7	c.283-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		3
HMGA2	ENST00000539662.1	c.*151+933T>C		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00802 AC: 1221 AN: 152164 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0393

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00976

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00592 AC: 757 AN: 127864 Hom.: 2 AF XY: 0.00598 AC XY: 419 AN XY: 70022

Gnomad AFR exome AF: 0.000986

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00630

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00251

Gnomad FIN exome AF: 0.0344

Gnomad NFE exome AF: 0.00843

Gnomad OTH exome AF: 0.00577

GnomAD4 exome AF: 0.00821 AC: 11338 AN: 1380820 Hom.: 52 Cov.: 29 AF XY: 0.00810 AC XY: 5519 AN XY: 681488

Gnomad4 AFR exome AF: 0.00124

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00628

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00229

Gnomad4 FIN exome AF: 0.0338

Gnomad4 NFE exome AF: 0.00868

Gnomad4 OTH exome AF: 0.00736

GnomAD4 genome AF: 0.00802 AC: 1221 AN: 152282 Hom.: 16 Cov.: 32 AF XY: 0.00905 AC XY: 674 AN XY: 74478

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0393

Gnomad4 NFE AF: 0.00976

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00953 Hom.: 2

Bravo AF: 0.00461

Asia WGS AF: 0.00173 AC: 6 AN: 3474

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

HMGA2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	2.8
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000067
dbscSNV1_RF	Benign	0.024
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

Publications

LitVar

Other links and lift over

dbSNP: rs142432942; hg19: chr12-66346128;