X-150987840-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005342.4(HMGB3):c.529C>T(p.Arg177Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,199,671 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.0000083 ( 0 hom. 2 hem. )

Consequence

HMGB3
NM_005342.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.53

Variant links:

Genes affected

HMGB3 (HGNC:5004): (high mobility group box 3) This gene encodes a member of a family of proteins containing one or more high mobility group DNA-binding motifs. The encoded protein plays an important role in maintaining stem cell populations, and may be aberrantly expressed in tumor cells. A mutation in this gene was associated with microphthalmia, syndromic 13. There are numerous pseudogenes of this gene on multiple chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

HMGB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22943974).

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGB3	NM_005342.4 link	c.529C>T	p.Arg177Trp	missense_variant	Exon 5 of 5	ENST00000325307.12	NP_005333.2	O15347

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HMGB3	ENST00000325307.12 link	c.529C>T	p.Arg177Trp	missense_variant	Exon 5 of 5	1	NM_005342.4	ENSP00000359393.3	O15347
HMGB3	ENST00000448905.6 link	c.529C>T	p.Arg177Trp	missense_variant	Exon 5 of 5	1		ENSP00000442758.1	O15347
HMGB3	ENST00000455596.5 link	c.529C>T	p.Arg177Trp	missense_variant	Exon 5 of 5	1		ENSP00000405601.1	E7EQU1
HMGB3	ENST00000419110.5 link	c.529C>T	p.Arg177Trp	missense_variant	Exon 5 of 5	3		ENSP00000410354.1	E7ES08

Frequencies

GnomAD3 genomes

AF:

0.0000274

AC:

AN:

109518

Hom.:

Cov.:

AF XY:

0.0000624

AC XY:

AN XY:

32034

show subpopulations

Gnomad AFR

AF:

0.0000668

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:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000112

AC:

AN:

179257

Hom.:

AF XY:

0.0000153

AC XY:

AN XY:

65419

show subpopulations

Gnomad AFR exome

AF:

0.0000764

Gnomad AMR exome

AF:

0.00

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:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000826

AC:

AN:

1090153

Hom.:

Cov.:

AF XY:

0.00000559

AC XY:

AN XY:

357793

show subpopulations

Gnomad4 AFR exome

AF:

0.0000760

Gnomad4 AMR exome

AF:

0.00

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:

0.00000596

Gnomad4 OTH exome

AF:

0.0000436

GnomAD4 genome

AF:

0.0000274

AC:

AN:

109518

Hom.:

Cov.:

AF XY:

0.0000624

AC XY:

AN XY:

32034

show subpopulations

Gnomad4 AFR

AF:

0.0000668

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:

0.0000190

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.529C>T (p.R177W) alteration is located in exon 5 (coding exon 4) of the HMGB3 gene. This alteration results from a C to T substitution at nucleotide position 529, causing the arginine (R) at amino acid position 177 to be replaced by a tryptophan (W). 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

Uncertain

0.45

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.42

DEOGEN2

Benign

0.074

T;T;.;T

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.21

T;.;T;T

M_CAP

Benign

0.063

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

0.0

.;N;.;N

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.3

N;N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.12

T;T;T;T

Sift4G

Benign

0.063

T;T;T;T

Polyphen

0.014

.;B;.;B

Vest4

0.39, 0.34

MutPred

0.21

Gain of ubiquitination at K178 (P = 0.0798);Gain of ubiquitination at K178 (P = 0.0798);Gain of ubiquitination at K178 (P = 0.0798);Gain of ubiquitination at K178 (P = 0.0798);

MVP

0.79

MPC

0.89

ClinPred

0.081

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.41

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

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