1-33864316-C-T

Variant names:

• chr1-33864316-C-T
• rs1434180841
• NM_001379301.1:c.125C>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.125C>T​(p.Ser42Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HMGB4 NM_001379301.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.56

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, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGB4	NM_001379301.1	c.125C>T	p.Ser42Phe	missense_variant	Exon 1 of 1	ENST00000681531.1	NP_001366230.1
CSMD2	NM_001281956.2	c.921-17320G>A		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.125C>T	p.Ser42Phe	missense_variant	Exon 1 of 1		NM_001379301.1	ENSP00000505691.1
CSMD2	ENST00000373381.9	c.921-17320G>A		intron_variant	Intron 5 of 70	1	NM_001281956.2	ENSP00000362479.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461710 Hom.: 0 Cov.: 63 AF XY: 0.00000138 AC XY: 1 AN XY: 727128

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.125C>T (p.S42F) alteration is located in exon 2 (coding exon 1) of the HMGB4 gene. This alteration results from a C to T substitution at nucleotide position 125, causing the serine (S) at amino acid position 42 to be replaced by a phenylalanine (F). 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	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	.;T
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	3.3	M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.78
MutPred		0.78		Loss of disorder (P = 0.0095);Loss of disorder (P = 0.0095);
MVP		0.69
MPC		0.061
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.89
gMVP		0.42

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: rs1434180841; hg19: chr1-34329917; COSMIC: COSV53922342; COSMIC: COSV53922342;