Genetic Variant NM_014983.3:c.310C>T (chr5-150006645-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014983.3(HMGXB3):c.310C>T(p.Pro104Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000715 in 1,398,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

HMGXB3
NM_014983.3 missense, splice_region

Scores

Splicing: ADA: 0.9998

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.73

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Tourette syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

HMGXB3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014983.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGXB3	NM_014983.3	MANE Select	c.310C>T	p.Pro104Ser	missense splice_region	Exon 3 of 20	NP_055798.3	Q12766
	HMGXB3	NM_001366501.2		c.310C>T	p.Pro104Ser	missense splice_region	Exon 3 of 19	NP_001353430.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMGXB3	ENST00000502717.6	TSL:1 MANE Select	c.310C>T	p.Pro104Ser	missense splice_region	Exon 3 of 20	ENSP00000421917.1	Q12766
HMGXB3	ENST00000613459.4	TSL:5	c.1048C>T	p.Pro350Ser	missense splice_region	Exon 4 of 21	ENSP00000479027.1	A0A8C8PVR7
HMGXB3	ENST00000971018.1		c.310C>T	p.Pro104Ser	missense splice_region	Exon 3 of 21	ENSP00000641077.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1398476

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689704

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31456

American (AMR)

AF:

0.00

AC:

AN:

35470

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25110

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35730

South Asian (SAS)

AF:

0.00

AC:

AN:

79092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49498

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5566

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078486

Other (OTH)

AF:

0.00

AC:

AN:

58068

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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

Cov.:

ClinVar

ClinVar submissions

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

0.23

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0015

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0029

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.14

PhyloP100

3.7

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.9

REVEL

Benign

0.18

Sift

Benign

0.27

Sift4G

Benign

0.31

Polyphen

0.66

Vest4

0.19

MutPred

0.56

Gain of phosphorylation at P350 (P = 0.0519)

MVP

0.15

ClinPred

0.87

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.51

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.79

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over