dbSNP rs375793961: HMGA1:p.Ser99Leu (chr6-34244856-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_145899.3(HMGA1):c.296C>T(p.Ser99Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,570,114 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: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

HMGA1
NM_145899.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.53

Publications

1 publications found

Variant links:

Genes affected

HMGA1 (HGNC:5010): (high mobility group AT-hook 1) This gene encodes a chromatin-associated protein involved in the regulation of gene transcription, integration of retroviruses into chromosomes, and the metastatic progression of cancer cells. The encoded protein preferentially binds to the minor groove of AT-rich regions in double-stranded DNA. Multiple transcript variants encoding different isoforms have been found for this gene. Pseudogenes of this gene have been identified on multiple chromosomes. [provided by RefSeq, Jan 2016]

HMGA1 Gene-Disease associations (from GenCC):

type 2 diabetes mellitus
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

HMGA1 links:

ENSG00000295821 (HGNC:):

ENSG00000295821 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0980095).

BS2

High AC in GnomAd4 at 15 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145899.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMGA1	NM_145899.3	MANE Select	c.296C>T	p.Ser99Leu	missense	Exon 6 of 6	NP_665906.1	P17096-1
HMGA1	NM_001319078.2		c.296C>T	p.Ser99Leu	missense	Exon 5 of 5	NP_001306007.1	P17096-1
HMGA1	NM_001319079.2		c.296C>T	p.Ser99Leu	missense	Exon 6 of 6	NP_001306008.1	P17096-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMGA1	ENST00000311487.9	TSL:1 MANE Select	c.296C>T	p.Ser99Leu	missense	Exon 6 of 6	ENSP00000308227.4	P17096-1
HMGA1	ENST00000447654.5	TSL:1	c.296C>T	p.Ser99Leu	missense	Exon 5 of 5	ENSP00000399888.1	P17096-1
HMGA1	ENST00000347617.10	TSL:1	c.263C>T	p.Ser88Leu	missense	Exon 5 of 5	ENSP00000288245.9	P17096-2

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000490

AC:

AN:

183586

AF XY:

0.0000614

show subpopulations

Gnomad AFR exome

AF:

0.000540

Gnomad AMR exome

AF:

0.0000371

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000120

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000141

AC:

AN:

1418052

Hom.:

Cov.:

AF XY:

0.00000998

AC XY:

AN XY:

701310

show subpopulations

African (AFR)

AF:

0.000336

AC:

AN:

32700

American (AMR)

AF:

0.0000263

AC:

AN:

37994

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25378

East Asian (EAS)

AF:

0.00

AC:

AN:

37806

South Asian (SAS)

AF:

0.00

AC:

AN:

80718

European-Finnish (FIN)

AF:

0.0000593

AC:

AN:

50570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4204

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1090006

Other (OTH)

AF:

0.0000511

AC:

AN:

58676

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.000290

AC:

AN:

41398

American (AMR)

AF:

0.0000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000965

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000336

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Benign

-0.0025

Eigen_PC

Benign

0.038

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.81

M_CAP

Benign

0.018

MetaRNN

Benign

0.098

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.85

PhyloP100

4.5

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.091

Sift

Benign

0.59

Sift4G

Benign

0.19

Polyphen

0.83

Vest4

0.47

MVP

0.49

MPC

1.3

ClinPred

0.12

GERP RS

2.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

Varity_R

0.093

gMVP

0.63

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over