X-150987804-A-C

Position:

• chrX-150987804-A-C

Variant summary

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

The NM_005342.4(HMGB3):​c.493A>C​(p.Lys165Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000183 in 1,093,987 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: HMGB3 NM_005342.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.16

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.493A>C	p.Lys165Gln	missense_variant	5/5	ENST00000325307.12	NP_005333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGB3	ENST00000325307.12	c.493A>C	p.Lys165Gln	missense_variant	5/5	1	NM_005342.4	ENSP00000359393.3
HMGB3	ENST00000448905.6	c.493A>C	p.Lys165Gln	missense_variant	5/5	1		ENSP00000442758.1
HMGB3	ENST00000455596.5	c.493A>C	p.Lys165Gln	missense_variant	5/5	1		ENSP00000405601.1
HMGB3	ENST00000419110.5	c.493A>C	p.Lys165Gln	missense_variant	5/5	3		ENSP00000410354.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1093987 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 360383

Gnomad4 AFR exome AF: 0.0000380

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000218

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

Jan 26, 2022

The c.493A>C (p.K165Q) alteration is located in exon 5 (coding exon 4) of the HMGB3 gene. This alteration results from a A to C substitution at nucleotide position 493, causing the lysine (K) at amino acid position 165 to be replaced by a glutamine (Q). 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	0.25
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.056	T;T;.;T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;.;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	0.0	.;N;.;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.073	T;T;T;T
Sift4G	Benign	0.062	T;T;T;T
Polyphen		0.39	.;B;.;B
Vest4		0.29, 0.31
MutPred		0.42		Loss of methylation at K165 (P = 2e-04);Loss of methylation at K165 (P = 2e-04);Loss of methylation at K165 (P = 2e-04);Loss of methylation at K165 (P = 2e-04);
MVP		0.96
MPC		1.3
ClinPred		0.90	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-150156277;