1-33864475-G-A

Variant names:

• chr1-33864475-G-A
• rs1639811600
• NM_001379301.1:c.284G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001379301.1(HMGB4):​c.284G>A​(p.Arg95Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HMGB4 NM_001379301.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16

Genes affected

HMGB4 (HGNC:24954): (high mobility group box 4) Predicted to enable DNA binding activity, bending. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

CSMD2 (HGNC:19290): (CUB and Sushi multiple domains 2) The protein encoded by this gene is thought to be involved in the control of complement cascade of the immune system. Defects in this gene have been associated with schizophrenia. This gene may act as a tumor suppressor for colorectal cancer. [provided by RefSeq, Jan 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27178055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGB4	NM_001379301.1	c.284G>A	p.Arg95Gln	missense_variant	Exon 1 of 1	ENST00000681531.1	NP_001366230.1
CSMD2	NM_001281956.2	c.921-17479C>T		intron_variant	Intron 5 of 70	ENST00000373381.9	NP_001268885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGB4	ENST00000681531.1	c.284G>A	p.Arg95Gln	missense_variant	Exon 1 of 1		NM_001379301.1	ENSP00000505691.1
CSMD2	ENST00000373381.9	c.921-17479C>T		intron_variant	Intron 5 of 70	1	NM_001281956.2	ENSP00000362479.4

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461282 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726914

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.284G>A (p.R95Q) alteration is located in exon 2 (coding exon 1) of the HMGB4 gene. This alteration results from a G to A substitution at nucleotide position 284, causing the arginine (R) at amino acid position 95 to be replaced by a glutamine (Q). 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	0.14
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D
Eigen	Benign	-0.082
Eigen_PC	Benign	-0.069
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.74	.;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.016	D;D
Sift4G	Uncertain	0.023	D;D
Vest4		0.13
MVP		0.92
MPC		0.010
ClinPred		0.98	D
GERP RS		3.7
Varity_R		0.20
gMVP		0.27

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: rs1639811600; hg19: chr1-34330076;