NM_005342.4:c.529C>T

Variant names:

• chrX-150987840-C-T
• rs372194723
• NM_005342.4:c.529C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005342.4(HMGB3):​c.529C>T​(p.Arg177Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,199,671 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.0000083 (0 hom. 2 hem.)
• Consequence: HMGB3 NM_005342.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53
• Publications: 1 publications found

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]

HMGB3 Gene-Disease associations (from GenCC):

• X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome

  Inheritance: XL, Unknown Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22943974).
• BS2: High Hemizygotes in GnomAd4 at 2 XL,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005342.4. 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
	HMGB3	NM_005342.4	MANE Select	c.529C>T	p.Arg177Trp	missense	Exon 5 of 5	NP_005333.2	O15347
	HMGB3	NM_001440773.1		c.595C>T	p.Arg199Trp	missense	Exon 5 of 5	NP_001427702.1
	HMGB3	NM_001301231.2		c.589C>T	p.Arg197Trp	missense	Exon 5 of 5	NP_001288160.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGB3	ENST00000325307.12	TSL:1 MANE Select	c.529C>T	p.Arg177Trp	missense	Exon 5 of 5	ENSP00000359393.3	O15347
	HMGB3	ENST00000448905.6	TSL:1	c.529C>T	p.Arg177Trp	missense	Exon 5 of 5	ENSP00000442758.1	O15347
	HMGB3	ENST00000455596.5	TSL:1	c.529C>T	p.Arg177Trp	missense	Exon 5 of 5	ENSP00000405601.1	E7EQU1

Frequencies

GnomAD3 genomes AF: 0.0000274 AC: 3 AN: 109518 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000668

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000190

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000112 AC: 2 AN: 179257 AF XY: 0.0000153

Gnomad AFR exome AF: 0.0000764

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000826 AC: 9 AN: 1090153 Hom.: 0 Cov.: 29 AF XY: 0.00000559 AC XY: 2 AN XY: 357793

African (AFR) AF: 0.0000760 AC: 2 AN: 26306

American (AMR) AF: 0.00 AC: 0 AN: 35155

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19298

East Asian (EAS) AF: 0.00 AC: 0 AN: 30176

South Asian (SAS) AF: 0.00 AC: 0 AN: 53582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37099

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3464

European-Non Finnish (NFE) AF: 0.00000596 AC: 5 AN: 839222

Other (OTH) AF: 0.0000436 AC: 2 AN: 45851

GnomAD4 genome AF: 0.0000274 AC: 3 AN: 109518 Hom.: 0 Cov.: 22 AF XY: 0.0000624 AC XY: 2 AN XY: 32034

African (AFR) AF: 0.0000668 AC: 2 AN: 29929

American (AMR) AF: 0.00 AC: 0 AN: 10170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2630

East Asian (EAS) AF: 0.00 AC: 0 AN: 3519

South Asian (SAS) AF: 0.00 AC: 0 AN: 2510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5675

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000190 AC: 1 AN: 52716

Other (OTH) AF: 0.00 AC: 0 AN: 1456

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Benign	0.42
DEOGEN2	Benign	0.074	T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.30
Sift	Benign	0.12	T
Sift4G	Benign	0.063	T
Polyphen		0.014	B
Vest4		0.39
MutPred		0.21		Gain of ubiquitination at K178 (P = 0.0798)
MVP		0.79
MPC		0.89
ClinPred		0.081	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.41
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs372194723; hg19: chrX-150156313;