12-65951407-C-G

Position:

chr12-65951407-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000403681.7(HMGA2):c.274C>G(p.Pro92Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000453 in 1,529,608 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 1 hom. )

Consequence

HMGA2
ENST00000403681.7 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.32

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0063559413).

BP6

Variant 12-65951407-C-G is Benign according to our data. Variant chr12-65951407-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 784302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 327 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGA2	NM_003483.6 linkuse as main transcript	c.274C>G	p.Pro92Ala	missense_variant	4/5	ENST00000403681.7	NP_003474.1
HMGA2	NM_001300918.1 linkuse as main transcript	c.274C>G	p.Pro92Ala	missense_variant	4/5		NP_001287847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGA2	ENST00000403681.7 linkuse as main transcript	c.274C>G	p.Pro92Ala	missense_variant	4/5	1	NM_003483.6	ENSP00000384026	P1	P52926-1
HMGA2	ENST00000541363.5 linkuse as main transcript	c.274C>G	p.Pro92Ala	missense_variant	4/4	1		ENSP00000439317
HMGA2	ENST00000393577.7 linkuse as main transcript	c.274C>G	p.Pro92Ala	missense_variant	4/5	3		ENSP00000377205
HMGA2	ENST00000539662.1 linkuse as main transcript	c.*143C>G		3_prime_UTR_variant, NMD_transcript_variant	4/5	3		ENSP00000440919

Frequencies

GnomAD3 genomes

AF:

0.00215

AC:

327

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00758

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.0000441

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000475

AC:

AN:

158020

Hom.:

AF XY:

0.000407

AC XY:

AN XY:

83464

show subpopulations

Gnomad AFR exome

AF:

0.00655

Gnomad AMR exome

AF:

0.000535

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000965

Gnomad OTH exome

AF:

0.000455

GnomAD4 exome

AF:

0.000266

AC:

366

AN:

1377450

Hom.:

Cov.:

AF XY:

0.000254

AC XY:

173

AN XY:

680112

show subpopulations

Gnomad4 AFR exome

AF:

0.00646

Gnomad4 AMR exome

AF:

0.000594

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:

0.0000904

Gnomad4 OTH exome

AF:

0.000753

GnomAD4 genome

AF:

0.00215

AC:

327

AN:

152158

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

161

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00756

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000436

Hom.:

Bravo

AF:

0.00236

ExAC

AF:

0.000227

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

HMGA2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Uncertain

0.66

D;T;.

Eigen

Uncertain

0.64

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.71

T;T;T

M_CAP

Benign

0.0088

MetaRNN

Benign

0.0064

T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

1.1

L;.;.

MutationTaster

Benign

0.83

D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.2

N;N;N

REVEL

Benign

0.29

Sift

Benign

0.059

T;D;D

Sift4G

Benign

0.17

T;T;T

Polyphen

0.99

D;D;.

Vest4

0.35

MVP

0.39

MPC

1.7

ClinPred

0.036

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.096

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over