X-150985715-C-T

Position:

• chrX-150985715-C-T

Variant summary

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

The NM_005342.4(HMGB3):​c.116C>T​(p.Ala39Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: HMGB3 NM_005342.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.78

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]

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	Protein	UniProt
HMGB3	NM_005342.4	c.116C>T	p.Ala39Val	missense_variant	2/5	ENST00000325307.12	NP_005333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGB3	ENST00000325307.12	c.116C>T	p.Ala39Val	missense_variant	2/5	1	NM_005342.4	ENSP00000359393.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

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

Feb 10, 2022

The c.116C>T (p.A39V) alteration is located in exon 2 (coding exon 1) of the HMGB3 gene. This alteration results from a C to T substitution at nucleotide position 116, causing the alanine (A) at amino acid position 39 to be replaced by a valine (V). 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	Pathogenic	0.85
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.025	T;T;.;T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;.;T;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.46	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	.;M;.;M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.9	D;D;D;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.028	D;D;D;D;D
Sift4G	Uncertain	0.027	D;D;D;D;T
Polyphen		0.64	.;P;.;P;.
Vest4		0.46
MutPred		0.43		Gain of methylation at K44 (P = 0.0982);Gain of methylation at K44 (P = 0.0982);Gain of methylation at K44 (P = 0.0982);Gain of methylation at K44 (P = 0.0982);Gain of methylation at K44 (P = 0.0982);
MVP		0.59
MPC		1.2
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.45
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chrX-150154188; COSMIC: COSV57486218;