Genetic Variant HMGXB4:p.Ser279Gly (chr22-35265223-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001003681.3(HMGXB4):c.835A>G(p.Ser279Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HMGXB4
NM_001003681.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.985

Publications

0 publications found

Variant links:

Genes affected

HMGXB4 (HGNC:5003): (HMG-box containing 4) High mobility group (HMG) proteins are nonhistone chromosomal proteins. See HMG2 (MIM 163906) for additional information on HMG proteins.[supplied by OMIM, Nov 2010]

HMGXB4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05820626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGXB4	NM_001003681.3 link	c.835A>G	p.Ser279Gly	missense_variant	Exon 5 of 11	ENST00000216106.6	NP_001003681.1	Q9UGU5Q7Z641

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGXB4	ENST00000216106.6 link	c.835A>G	p.Ser279Gly	missense_variant	Exon 5 of 11	5	NM_001003681.3	ENSP00000216106.5		Q9UGU5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251210

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

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

Dec 25, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.835A>G (p.S279G) alteration is located in exon 5 (coding exon 4) of the HMGXB4 gene. This alteration results from a A to G substitution at nucleotide position 835, causing the serine (S) at amino acid position 279 to be replaced by a glycine (G). 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

0.055

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.064

T;.;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.64

T;T;T

M_CAP

Benign

0.0028

MetaRNN

Benign

0.058

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.26

.;.;N

PhyloP100

0.98

PrimateAI

Benign

0.40

PROVEAN

Benign

1.7

N;N;N

REVEL

Benign

0.014

Sift

Benign

0.32

T;T;T

Sift4G

Benign

0.43

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.078

MutPred

0.20

.;.;Loss of phosphorylation at S279 (P = 0.0335);

MVP

0.41

MPC

0.091

ClinPred

0.047

GERP RS

2.3

Varity_R

0.028

gMVP

0.13

Mutation Taster

=92/8

polymorphism

(source)

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

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22-35265223-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over