Genetic Variant HMGB4:p.Ser14Phe (chr1-33864232-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001379301.1(HMGB4):c.41C>T(p.Ser14Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,008 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. S14C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HMGB4
NM_001379301.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.90

Publications

0 publications found

Variant links:

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]

HMGB4 links:

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]

CSMD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379301.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMGB4	NM_001379301.1	MANE Select	c.41C>T	p.Ser14Phe	missense	Exon 1 of 1	NP_001366230.1	Q8WW32
CSMD2	NM_001281956.2	MANE Select	c.921-17236G>A		intron	N/A	NP_001268885.1	Q7Z408-4
HMGB4	NM_145205.6		c.41C>T	p.Ser14Phe	missense	Exon 2 of 2	NP_660206.2	Q8WW32

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMGB4	ENST00000681531.1	MANE Select	c.41C>T	p.Ser14Phe	missense	Exon 1 of 1	ENSP00000505691.1	Q8WW32
HMGB4	ENST00000519684.5	TSL:1	c.41C>T	p.Ser14Phe	missense	Exon 2 of 2	ENSP00000429214.1	Q8WW32
CSMD2	ENST00000373381.9	TSL:1 MANE Select	c.921-17236G>A		intron	N/A	ENSP00000362479.4	Q7Z408-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460008

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33298

American (AMR)

AF:

0.00

AC:

AN:

44350

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

85740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111616

Other (OTH)

AF:

0.00

AC:

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.75

M_CAP

Benign

0.038

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.9

PhyloP100

3.9

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.32

Sift

Uncertain

0.017

Sift4G

Benign

0.12

Vest4

0.85

MutPred

0.67

Loss of disorder (P = 0.0307)

MVP

0.51

MPC

0.061

ClinPred

0.99

GERP RS

4.5

PromoterAI

-0.0023

Neutral

(source)

Varity_R

0.75

gMVP

0.56

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over