Genetic Variant HMGA1:p.Ser99Leu (chr6-34244856-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity HMGA1_HUMAN

BP4

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

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGA1	NM_145899.3 link	c.296C>T	p.Ser99Leu	missense_variant	Exon 6 of 6	ENST00000311487.9	NP_665906.1	P17096-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGA1	ENST00000311487.9 link	c.296C>T	p.Ser99Leu	missense_variant	Exon 6 of 6	1	NM_145899.3	ENSP00000308227.4		P17096-1

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

GnomAD3 exomes

AF:

0.0000490

AC:

AN:

183586

Hom.:

AF XY:

0.0000614

AC XY:

AN XY:

97664

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 SAS 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

Gnomad4 AFR exome

AF:

0.000336

Gnomad4 AMR exome

AF:

0.0000263

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000593

Gnomad4 NFE exome

AF:

0.00000183

Gnomad4 OTH exome

AF:

0.0000511

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.000290

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.296C>T (p.S99L) alteration is located in exon 6 (coding exon 4) of the HMGA1 gene. This alteration results from a C to T substitution at nucleotide position 296, causing the serine (S) at amino acid position 99 to be replaced by a leucine (L). 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

0.18

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;.;.;T;.

Eigen

Benign

-0.0025

Eigen_PC

Benign

0.038

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.81

T;.;.;.;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.098

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.85

L;.;.;L;.

PROVEAN

Uncertain

-2.8

D;D;D;D;D

REVEL

Benign

0.091

Sift

Benign

0.59

T;T;T;T;T

Sift4G

Benign

0.19

T;T;T;T;T

Polyphen

0.83

P;P;P;P;P

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

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

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