rs536684668

Variant names:

• chr1-33864285-C-A
• NM_001379301.1:c.94C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-33864285-C-A
• chr1-33864285-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001379301.1(HMGB4):​c.94C>A​(p.Pro32Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P32S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HMGB4 NM_001379301.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.26

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGB4	NM_001379301.1	c.94C>A	p.Pro32Thr	missense_variant	Exon 1 of 1	ENST00000681531.1	NP_001366230.1
CSMD2	NM_001281956.2	c.921-17289G>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.94C>A	p.Pro32Thr	missense_variant	Exon 1 of 1		NM_001379301.1	ENSP00000505691.1
CSMD2	ENST00000373381.9	c.921-17289G>T		intron_variant	Intron 5 of 70	1	NM_001281956.2	ENSP00000362479.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461026 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726772

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T;T
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.64	.;T
M_CAP	Benign	0.025	T
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Pathogenic	3.4	M;M
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-7.2	D;D
REVEL	Benign	0.29
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.071	T;T
Vest4		0.61
MutPred		0.75		Gain of MoRF binding (P = 0.0564);Gain of MoRF binding (P = 0.0564);
MVP		0.61
MPC		0.061
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.81
gMVP		0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-34329886;