chr5-150010268-C-A

Position:

• chr5-150010268-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014983.3(HMGXB3):​c.470C>A​(p.Ser157Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,399,516 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HMGXB3 NM_014983.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13575679).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGXB3	NM_014983.3	c.470C>A	p.Ser157Tyr	missense_variant	4/20	ENST00000502717.6
HMGXB3	XM_047416963.1	c.470C>A	p.Ser157Tyr	missense_variant	4/12
HMGXB3	NM_001366501.2	c.313-1987C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGXB3	ENST00000502717.6	c.470C>A	p.Ser157Tyr	missense_variant	4/20	1	NM_014983.3	P2
HMGXB3	ENST00000613459.4	c.1208C>A	p.Ser403Tyr	missense_variant	5/21	5		A2
HMGXB3	ENST00000503427.5	c.470C>A	p.Ser157Tyr	missense_variant	4/21	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1399516 Hom.: 0 Cov.: 32 AF XY: 0.00000435 AC XY: 3 AN XY: 690256

Gnomad4 AFR exome AF: 0.00

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: 9.27e-7

Gnomad4 OTH exome AF: 0.0000345

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

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

Jun 06, 2023

The c.470C>A (p.S157Y) alteration is located in exon 4 (coding exon 3) of the HMGXB3 gene. This alteration results from a C to A substitution at nucleotide position 470, causing the serine (S) at amino acid position 157 to be replaced by a tyrosine (Y). 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	0.11
BayesDel_addAF	Benign	-0.0091	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0082	T;T;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.47	T
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.85	P;.;.
Vest4		0.13
MVP		0.25
ClinPred		0.58	D
GERP RS		5.0
Varity_R		0.16
gMVP		0.67

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: rs753868898; hg19: chr5-149389831;