NM_001003681.3:c.598G>A

Variant names:

• chr22-35264986-G-A
• NM_001003681.3:c.598G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001003681.3(HMGXB4):​c.598G>A​(p.Glu200Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HMGXB4 NM_001003681.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.55
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26437074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGXB4	NM_001003681.3	c.598G>A	p.Glu200Lys	missense_variant	Exon 5 of 11	ENST00000216106.6	NP_001003681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGXB4	ENST00000216106.6	c.598G>A	p.Glu200Lys	missense_variant	Exon 5 of 11	5	NM_001003681.3	ENSP00000216106.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.598G>A (p.E200K) alteration is located in exon 5 (coding exon 4) of the HMGXB4 gene. This alteration results from a G to A substitution at nucleotide position 598, causing the glutamic acid (E) at amino acid position 200 to be replaced by a lysine (K). 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	Uncertain	0.53
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.068	T;.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.0	.;.;L
PhyloP100		6.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.070	T;T;T
Polyphen		0.77	.;.;P
Vest4		0.29
MutPred		0.23		.;.;Gain of MoRF binding (P = 0.0093);
MVP		0.75
MPC		0.46
ClinPred		0.78	D
GERP RS		5.9
Varity_R		0.56
gMVP		0.28
Mutation Taster		=64/36	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

hg19: chr22-35660979;