12-65951407-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003483.6(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 NM_003483.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.32

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 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 GnomAd at 327 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGA2	ENST00000403681.7	c.274C>G	p.Pro92Ala	missense_variant	4/5	1	NM_003483.6	P1
HMGA2	ENST00000541363.5	c.274C>G	p.Pro92Ala	missense_variant	4/4	1
HMGA2	ENST00000393577.7	c.274C>G	p.Pro92Ala	missense_variant	4/5	3
HMGA2	ENST00000539662.1	c.*143C>G		3_prime_UTR_variant, NMD_transcript_variant	4/5	3

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 327 AN: 152040 Hom.: 0 Cov.: 32

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: 75 AN: 158020 Hom.: 0 AF XY: 0.000407 AC XY: 34 AN XY: 83464

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.: 1 Cov.: 25 AF XY: 0.000254 AC XY: 173 AN XY: 680112

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.: 0 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74386

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.: 0

Bravo AF: 0.00236

ExAC AF: 0.000227 AC: 22

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

HMGA2-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	23
Dann	Benign	0.88
DEOGEN2	Uncertain	0.66	D;T;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.0064	T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	0.83	D;D;D
PrimateAI	Pathogenic	0.80	T
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	T
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

Other links and lift over

dbSNP: rs151017786; hg19: chr12-66345187;