rs1114167320

Variant names:

• chr12-65828077-CA-C
• rs1114167320
• NM_003483.6:c.189delA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001300919.1(HMGA2):​c.189delA​(p.Ala64LeufsTer47) 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 (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMGA2 NM_001300919.1 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.802
• Publications: 1 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-65828077-CA-C is Pathogenic according to our data. Variant chr12-65828077-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 253035.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001300919.1. 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.189delA	p.Ala64LeufsTer102	frameshift	Exon 2 of 5	NP_003474.1
	HMGA2	NM_001300919.1		c.189delA	p.Ala64LeufsTer47	frameshift	Exon 2 of 4	NP_001287848.1
	HMGA2	NM_001300918.1		c.189delA	p.Ala64LeufsTer65	frameshift	Exon 2 of 5	NP_001287847.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGA2	ENST00000403681.7	TSL:1 MANE Select	c.189delA	p.Ala64LeufsTer102	frameshift	Exon 2 of 5	ENSP00000384026.2
	HMGA2	ENST00000536545.5	TSL:1	c.189delA	p.Ala64LeufsTer47	frameshift	Exon 2 of 4	ENSP00000437621.1
	HMGA2	ENST00000354636.7	TSL:1	c.189delA	p.Ala64LeufsTer68	frameshift	Exon 2 of 4	ENSP00000346658.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.80
Mutation Taster		=13/187	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1114167320; hg19: chr12-66221857;