12-65828068-C-T

Position:

• chr12-65828068-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000403681.7(HMGA2):​c.179C>T​(p.Pro60Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HMGA2 ENST00000403681.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.25

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35407037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGA2	NM_003483.6	c.179C>T	p.Pro60Leu	missense_variant	2/5	ENST00000403681.7	NP_003474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGA2	ENST00000403681.7	c.179C>T	p.Pro60Leu	missense_variant	2/5	1	NM_003483.6	ENSP00000384026	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461140 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726932

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;.;.;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.9	L;L;L;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.8	D;D;D;N;D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0040	D;D;D;T;D;D;D
Sift4G	Uncertain	0.012	D;D;D;T;D;D;D
Polyphen		1.0	D;.;.;D;.;D;.
Vest4		0.63
MutPred		0.34		Loss of glycosylation at P60 (P = 0.0153);Loss of glycosylation at P60 (P = 0.0153);Loss of glycosylation at P60 (P = 0.0153);Loss of glycosylation at P60 (P = 0.0153);Loss of glycosylation at P60 (P = 0.0153);Loss of glycosylation at P60 (P = 0.0153);Loss of glycosylation at P60 (P = 0.0153);
MVP		0.58
MPC		1.9
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.53
gMVP		0.052

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-66221848;