12-65825285-T-G

Variant names:

• chr12-65825285-T-G
• rs1448432644
• NM_003483.6:c.15T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_003483.6(HMGA2):​c.15T>G​(p.Gly5Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HMGA2 NM_003483.6 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.25
• Publications: 0 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]

RPSAP52 (HGNC:):

RPSAP52 (HGNC:35752): (ribosomal protein SA pseudogene 52)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-65825285-T-G is Benign according to our data. Variant chr12-65825285-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3033836.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.25 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGA2	NM_003483.6	MANE Select	c.15T>G	p.Gly5Gly	synonymous	Exon 1 of 5	NP_003474.1	P52926-1
	HMGA2	NM_001300919.1		c.15T>G	p.Gly5Gly	synonymous	Exon 1 of 4	NP_001287848.1	Q1M183
	HMGA2	NM_001300918.1		c.15T>G	p.Gly5Gly	synonymous	Exon 1 of 5	NP_001287847.1	F5H2A4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGA2	ENST00000403681.7	TSL:1 MANE Select	c.15T>G	p.Gly5Gly	synonymous	Exon 1 of 5	ENSP00000384026.2	P52926-1
	HMGA2	ENST00000536545.5	TSL:1	c.15T>G	p.Gly5Gly	synonymous	Exon 1 of 4	ENSP00000437621.1	F5H6H0
	HMGA2	ENST00000354636.7	TSL:1	c.15T>G	p.Gly5Gly	synonymous	Exon 1 of 4	ENSP00000346658.3	P52926-2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151846 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000441 AC: 605 AN: 1373382 Hom.: 0 Cov.: 31 AF XY: 0.000384 AC XY: 260 AN XY: 677756

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000332 AC: 10 AN: 30152

American (AMR) AF: 0.00 AC: 0 AN: 35286

Ashkenazi Jewish (ASJ) AF: 0.0000807 AC: 2 AN: 24780

East Asian (EAS) AF: 0.0000286 AC: 1 AN: 34924

South Asian (SAS) AF: 0.0000894 AC: 7 AN: 78288

European-Finnish (FIN) AF: 0.0000531 AC: 2 AN: 37678

Middle Eastern (MID) AF: 0.000431 AC: 2 AN: 4636

European-Non Finnish (NFE) AF: 0.000526 AC: 563 AN: 1070392

Other (OTH) AF: 0.000314 AC: 18 AN: 57246

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 151846 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74150

African (AFR) AF: 0.00 AC: 0 AN: 41356

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67940

Other (OTH) AF: 0.00 AC: 0 AN: 2088

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	HMGA2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.6
DANN	Benign	0.42
PhyloP100		-1.3
PromoterAI		0.023	Neutral

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: rs1448432644; hg19: chr12-66219065;