12-65915116-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000354636.7(HMGA2):c.307A>G(p.Lys103Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,613,748 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (10 hom.)
• Consequence: HMGA2 ENST00000354636.7 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.467

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037813485).
• BP6: Variant 12-65915116-A-G is Benign according to our data. Variant chr12-65915116-A-G is described in ClinVar as [Benign]. Clinvar id is 3044402.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 413 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGA2	NM_003483.6	c.250-36267A>G		intron_variant		ENST00000403681.7
HMGA2	NM_003484.1	c.307A>G	p.Lys103Glu	missense_variant	4/4
HMGA2	NM_001300919.1	c.*202A>G		3_prime_UTR_variant	4/4
HMGA2	NM_001300918.1	c.250-36267A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGA2	ENST00000403681.7	c.250-36267A>G		intron_variant		1	NM_003483.6	P1

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 413 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00800

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00409

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00304 AC: 763 AN: 251342 Hom.: 2 AF XY: 0.00286 AC XY: 389 AN XY: 135822

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0101

Gnomad NFE exome AF: 0.00428

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00344 AC: 5025 AN: 1461402 Hom.: 10 Cov.: 31 AF XY: 0.00327 AC XY: 2375 AN XY: 727038

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.00383

Gnomad4 OTH exome AF: 0.00249

GnomAD4 genome AF: 0.00271 AC: 413 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.00285 AC XY: 212 AN XY: 74500

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00800

Gnomad4 NFE AF: 0.00409

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00346 Hom.: 2

Bravo AF: 0.00203

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00275 AC: 334

EpiCase AF: 0.00327

EpiControl AF: 0.00326

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HMGA2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 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
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	1.1
Dann	Benign	0.47
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PROVEAN	Benign	1.4	N
REVEL	Benign	0.040
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.53	T
Vest4		0.086
MVP		0.043
ClinPred		0.0082	T
GERP RS		-4.4

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: rs77970919; hg19: chr12-66308896;