Genetic Variant HMGN5:p.Met12Thr (chrX-81119798-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_030763.3(HMGN5):c.35T>C(p.Met12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000623 in 1,204,768 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M12V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., 10 hem., cov: 23)

Exomes 𝑓: 0.000034 ( 0 hom. 12 hem. )

Consequence

HMGN5
NM_030763.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.164

Publications

0 publications found

Variant links:

Genes affected

HMGN5 (HGNC:8013): (high mobility group nucleosome binding domain 5) This gene encodes a nuclear protein with similarities to the high mobility group proteins, HMG14 and HMG17, which suggests that this protein may function as a nucleosomal binding and transcriptional activating protein. [provided by RefSeq, Sep 2009]

HMGN5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00659883).

BS2

High Hemizygotes in GnomAd4 at 10 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030763.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGN5	NM_030763.3	MANE Select	c.35T>C	p.Met12Thr	missense	Exon 3 of 7	NP_110390.1	P82970

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMGN5	ENST00000358130.7	TSL:2 MANE Select	c.35T>C	p.Met12Thr	missense	Exon 3 of 7	ENSP00000350848.2	P82970
HMGN5	ENST00000430960.5	TSL:1	c.35T>C	p.Met12Thr	missense	Exon 2 of 6	ENSP00000399626.1	Q5JSL0
HMGN5	ENST00000916831.1		c.35T>C	p.Met12Thr	missense	Exon 2 of 7	ENSP00000586890.1

Frequencies

GnomAD3 genomes

AF:

0.000340

AC:

AN:

111918

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00117

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000950

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000665

GnomAD2 exomes

AF:

0.000109

AC:

AN:

182740

AF XY:

0.0000744

show subpopulations

Gnomad AFR exome

AF:

0.00152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000339

AC:

AN:

1092799

Hom.:

Cov.:

AF XY:

0.0000335

AC XY:

AN XY:

358393

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

26300

American (AMR)

AF:

0.0000284

AC:

AN:

35184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19339

East Asian (EAS)

AF:

0.00

AC:

AN:

30157

South Asian (SAS)

AF:

0.00

AC:

AN:

53950

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4119

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

837311

Other (OTH)

AF:

0.000131

AC:

AN:

45923

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.000339

AC:

AN:

111969

Hom.:

Cov.:

AF XY:

0.000293

AC XY:

AN XY:

34149

show subpopulations

African (AFR)

AF:

0.00117

AC:

AN:

30874

American (AMR)

AF:

0.0000949

AC:

AN:

10536

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3557

South Asian (SAS)

AF:

0.00

AC:

AN:

2699

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53156

Other (OTH)

AF:

0.000657

AC:

AN:

1522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.000170

Hom.:

Bravo

AF:

0.000283

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000124

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.12

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.0048

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.24

M_CAP

Benign

0.0037

MetaRNN

Benign

0.0066

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.090

PhyloP100

-0.16

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.70

REVEL

Benign

0.011

Sift

Benign

0.82

Sift4G

Benign

0.70

Polyphen

0.014

Vest4

0.16

MVP

0.38

MPC

0.021

ClinPred

0.0026

GERP RS

-0.95

Varity_R

0.061

gMVP

0.0094

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over