Genetic Variant HMGXB3:p.Pro116Leu (chr5-150010145-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014983.3(HMGXB3):c.347C>T(p.Pro116Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000322 in 1,551,468 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

HMGXB3
NM_014983.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.92

Variant links:

Genes affected

HMGXB3 (HGNC:28982): (HMG-box containing 3) This gene is one of the non-canonical high mobility group (HMG) genes. The encoded protein contains an HMG-box domain found in DNA binding proteins such as transcription factors and chromosomal proteins. [provided by RefSeq, Aug 2011]

HMGXB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGXB3	NM_014983.3 link	c.347C>T	p.Pro116Leu	missense_variant	Exon 4 of 20	ENST00000502717.6	NP_055798.3	Q12766Q562E5
HMGXB3	XM_047416963.1 link	c.347C>T	p.Pro116Leu	missense_variant	Exon 4 of 12		XP_047272919.1
HMGXB3	NM_001366501.2 link	c.313-2110C>T		intron_variant	Intron 3 of 18		NP_001353430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HMGXB3	ENST00000502717.6 link	c.347C>T	p.Pro116Leu	missense_variant	Exon 4 of 20	1	NM_014983.3	ENSP00000421917.1	Q12766
HMGXB3	ENST00000613459.4 link	c.1085C>T	p.Pro362Leu	missense_variant	Exon 5 of 21	5		ENSP00000479027.1	A0A8C8PVR7
HMGXB3	ENST00000503427.5 link	c.347C>T	p.Pro116Leu	missense_variant	Exon 4 of 21	5		ENSP00000422231.1	E9PEK0

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152096

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

GnomAD4 exome

AF:

0.00000286

AC:

AN:

1399372

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

690196

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:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000185

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74300

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.347C>T (p.P116L) alteration is located in exon 4 (coding exon 3) of the HMGXB3 gene. This alteration results from a C to T substitution at nucleotide position 347, causing the proline (P) at amino acid position 116 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

0.22

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.016

T;T;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.0029

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.97

L;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.6

.;D;D

REVEL

Uncertain

0.29

Sift

Uncertain

0.0040

.;D;D

Sift4G

Uncertain

0.013

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.53

MutPred

0.47

Gain of sheet (P = 0.0043);.;.;

MVP

0.47

ClinPred

0.89

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.37

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.37

Position offset: 12

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