5-150010222-C-T

Variant names:

• chr5-150010222-C-T
• rs577757155
• NM_014983.3:c.424C>T

Variant summary

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

The NM_014983.3(HMGXB3):​c.424C>T​(p.Arg142Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,551,850 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R142Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: HMGXB3 NM_014983.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35

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=0.0041986406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGXB3	NM_014983.3	c.424C>T	p.Arg142Trp	missense_variant	Exon 4 of 20	ENST00000502717.6	NP_055798.3
HMGXB3	XM_047416963.1	c.424C>T	p.Arg142Trp	missense_variant	Exon 4 of 12		XP_047272919.1
HMGXB3	NM_001366501.2	c.313-2033C>T		intron_variant	Intron 3 of 18		NP_001353430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGXB3	ENST00000502717.6	c.424C>T	p.Arg142Trp	missense_variant	Exon 4 of 20	1	NM_014983.3	ENSP00000421917.1
HMGXB3	ENST00000613459.4	c.1162C>T	p.Arg388Trp	missense_variant	Exon 5 of 21	5		ENSP00000479027.1
HMGXB3	ENST00000503427.5	c.424C>T	p.Arg142Trp	missense_variant	Exon 4 of 21	5		ENSP00000422231.1

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000178 AC: 28 AN: 157280 Hom.: 0 AF XY: 0.000168 AC XY: 14 AN XY: 83200

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.000162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000161 AC: 226 AN: 1399620 Hom.: 1 Cov.: 32 AF XY: 0.000161 AC XY: 111 AN XY: 690308

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.000112

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: 0.000161

Gnomad4 OTH exome AF: 0.000155

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000511 AC XY: 38 AN XY: 74432

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000388 Hom.: 0

Bravo AF: 0.000544

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000216 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.424C>T (p.R142W) alteration is located in exon 4 (coding exon 3) of the HMGXB3 gene. This alteration results from a C to T substitution at nucleotide position 424, causing the arginine (R) at amino acid position 142 to be replaced by a tryptophan (W). 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	0.10
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T;T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.0042	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.1	.;N;N
REVEL	Benign	0.044
Sift	Benign	0.065	.;T;T
Sift4G	Benign	0.066	T;T;T
Polyphen		0.014	B;.;.
Vest4		0.32
MVP		0.19
ClinPred		0.018	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.078
gMVP		0.65

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: rs577757155; hg19: chr5-149389785;