chr22-35265539-A-G

Position:

• chr22-35265539-A-G

Variant summary

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

The NM_001003681.3(HMGXB4):​c.1151A>G​(p.Asp384Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,455,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HMGXB4 NM_001003681.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.08

Genes affected

HMGXB4 (HGNC:5003): (HMG-box containing 4) High mobility group (HMG) proteins are nonhistone chromosomal proteins. See HMG2 (MIM 163906) for additional information on HMG proteins.[supplied by OMIM, Nov 2010]

HMGXB4 (HGNC:):

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
HMGXB4	NM_001003681.3	c.1151A>G	p.Asp384Gly	missense_variant	5/11	ENST00000216106.6	NP_001003681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGXB4	ENST00000216106.6	c.1151A>G	p.Asp384Gly	missense_variant	5/11	5	NM_001003681.3	ENSP00000216106.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1455616 Hom.: 0 Cov.: 37 AF XY: 0.00000414 AC XY: 3 AN XY: 724284

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Jul 30, 2024

The c.1151A>G (p.D384G) alteration is located in exon 5 (coding exon 4) of the HMGXB4 gene. This alteration results from a A to G substitution at nucleotide position 1151, causing the aspartic acid (D) at amino acid position 384 to be replaced by a glycine (G). 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	0.18
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	2.0	.;.;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.9	D;D;N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.038	D;D;T
Polyphen		0.99	.;.;D
Vest4		0.41
MutPred		0.24		.;.;Gain of relative solvent accessibility (P = 0.005);
MVP		0.76
MPC		0.27
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.16
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: -1

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: chr22-35661532;