5-150010208-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014983.3(HMGXB3):c.410G>C(p.Ser137Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMGXB3 NM_014983.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.745

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052115113).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGXB3	NM_014983.3	c.410G>C	p.Ser137Thr	missense_variant	4/20	ENST00000502717.6
HMGXB3	XM_047416963.1	c.410G>C	p.Ser137Thr	missense_variant	4/12
HMGXB3	NM_001366501.2	c.313-2047G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGXB3	ENST00000502717.6	c.410G>C	p.Ser137Thr	missense_variant	4/20	1	NM_014983.3	P2
HMGXB3	ENST00000613459.4	c.1148G>C	p.Ser383Thr	missense_variant	5/21	5		A2
HMGXB3	ENST00000503427.5	c.410G>C	p.Ser137Thr	missense_variant	4/21	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

May 16, 2023

The c.410G>C (p.S137T) alteration is located in exon 4 (coding exon 3) of the HMGXB3 gene. This alteration results from a G to C substitution at nucleotide position 410, causing the serine (S) at amino acid position 137 to be replaced by a threonine (T). 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	0.061
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	17
Dann	Benign	0.70
DEOGEN2	Benign	0.0021	T;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.079
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.052	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.55	N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.51	T
Sift4G	Benign	0.46	T;T;T
Polyphen		0.0070	B;.;.
Vest4		0.060
MutPred		0.18		Gain of relative solvent accessibility (P = 0.0479);.;.;
MVP		0.13
ClinPred		0.067	T
GERP RS		4.1
Varity_R		0.069
gMVP		0.44

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

Other links and lift over

dbSNP: rs1283462636; hg19: chr5-149389771; COSMIC: COSV105366465; COSMIC: COSV105366465;