Variant 12-65838532-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000403681.7(HMGA2):c.212C>T(p.Thr71Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,611,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

HMGA2
ENST00000403681.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.02

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1463117).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGA2	NM_003483.6 linkuse as main transcript	c.212C>T	p.Thr71Ile	missense_variant	3/5	ENST00000403681.7	NP_003474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGA2	ENST00000403681.7 linkuse as main transcript	c.212C>T	p.Thr71Ile	missense_variant	3/5	1	NM_003483.6	ENSP00000384026	P1	P52926-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250920

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135648

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1459822

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726238

show subpopulations

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:

0.00000810

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2021

The c.212C>T (p.T71I) alteration is located in exon 3 (coding exon 3) of the HMGA2 gene. This alteration results from a C to T substitution at nucleotide position 212, causing the threonine (T) at amino acid position 71 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.73

D;.;.;.;.;T;.

Eigen

Benign

-0.13

Eigen_PC

Benign

0.027

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.79

T;T;T;T;T;T;T

M_CAP

Benign

0.0071

MetaRNN

Benign

0.15

T;T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.8

L;L;L;.;L;.;.

MutationTaster

Benign

0.81

D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.4

D;D;D;N;D;D;D

REVEL

Benign

0.019

Sift

Benign

0.097

T;T;T;T;T;T;T

Sift4G

Uncertain

0.031

D;D;D;T;D;D;D

Polyphen

0.020

B;.;.;B;.;B;.

Vest4

0.33

MutPred

0.31

Loss of phosphorylation at T71 (P = 0.0065);Loss of phosphorylation at T71 (P = 0.0065);Loss of phosphorylation at T71 (P = 0.0065);Loss of phosphorylation at T71 (P = 0.0065);Loss of phosphorylation at T71 (P = 0.0065);Loss of phosphorylation at T71 (P = 0.0065);Loss of phosphorylation at T71 (P = 0.0065);

MVP

0.32

MPC

1.1

ClinPred

0.62

GERP RS

4.5

Varity_R

0.11

gMVP

0.047

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