chr12-65825316-C-CA

Variant names:

• chr12-65825316-C-CA
• rs2120807666
• NM_003483.6:c.47dupA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_003483.6(HMGA2):​c.47dupA​(p.Gln18ThrfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HMGA2 NM_003483.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.11
• 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_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-65825316-C-CA is Pathogenic according to our data. Variant chr12-65825316-C-CA is described in ClinVar as Pathogenic. ClinVar VariationId is 1679403.Status of the report is criteria_provided_single_submitter, 1 stars.

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.47dupA	p.Gln18ThrfsTer25	frameshift	Exon 1 of 5	NP_003474.1	P52926-1
	HMGA2	NM_001300919.1		c.47dupA	p.Gln18ThrfsTer25	frameshift	Exon 1 of 4	NP_001287848.1	Q1M183
	HMGA2	NM_001300918.1		c.47dupA	p.Gln18ThrfsTer25	frameshift	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.47dupA	p.Gln18ThrfsTer25	frameshift	Exon 1 of 5	ENSP00000384026.2	P52926-1
	HMGA2	ENST00000536545.5	TSL:1	c.47dupA	p.Gln18ThrfsTer25	frameshift	Exon 1 of 4	ENSP00000437621.1	F5H6H0
	HMGA2	ENST00000354636.7	TSL:1	c.47dupA	p.Gln18ThrfsTer25	frameshift	Exon 1 of 4	ENSP00000346658.3	P52926-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Silver-Russell syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2120807666; hg19: chr12-66219096;