5-150006645-C-T

Variant summary

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

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

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]

ACMG classification

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/exons	MANE	UniProt
HMGXB3	NM_014983.3	c.310C>T	p.Pro104Ser	missense_variant, splice_region_variant	3/20	ENST00000502717.6
HMGXB3	NM_001366501.2	c.310C>T	p.Pro104Ser	missense_variant, splice_region_variant	3/19
HMGXB3	XM_047416963.1	c.310C>T	p.Pro104Ser	missense_variant, splice_region_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGXB3	ENST00000502717.6	c.310C>T	p.Pro104Ser	missense_variant, splice_region_variant	3/20	1	NM_014983.3	P2
HMGXB3	ENST00000613459.4	c.1048C>T	p.Pro350Ser	missense_variant, splice_region_variant	4/21	5		A2
HMGXB3	ENST00000503427.5	c.310C>T	p.Pro104Ser	missense_variant, splice_region_variant	3/21	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398476 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689704

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2023

The c.310C>T (p.P104S) alteration is located in exon 3 (coding exon 2) of the HMGXB3 gene. This alteration results from a C to T substitution at nucleotide position 310, causing the proline (P) at amino acid position 104 to be replaced by a serine (S). 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	0.23
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0015	T;T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.14	N;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.66	P;.;.
Vest4		0.19
MutPred		0.56		Gain of phosphorylation at P350 (P = 0.0519);.;.;
MVP		0.15
ClinPred		0.87	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-149386208;