NM_005323.4:c.40G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005323.4(H1-6):c.40G>C(p.Val14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 1,613,538 control chromosomes in the GnomAD database, including 210,636 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.47 ( 17716 hom., cov: 32)

Exomes 𝑓: 0.51 ( 192920 hom. )

Consequence

H1-6
NM_005323.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.62

Publications

39 publications found

Variant links:

Genes affected

H1-6 (HGNC:4720): (H1.6 linker histone, cluster member) Histones are basic nuclear proteins responsible for nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H1 family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6. [provided by RefSeq, Aug 2015]

H1-6 links:

H2BC4 (HGNC:4757): (H2B clustered histone 4) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. The protein has antibacterial and antifungal antimicrobial activity. The main transcript variant of this gene is intronless and encodes a replication-dependent histone that is a member of the histone H2B family. This transcript variant lacks a polyA tail but instead contains a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6. [provided by RefSeq, Apr 2020]

H2BC4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.39349E-5).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005323.4. 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
	H1-6	NM_005323.4	MANE Select	c.40G>C	p.Val14Leu	missense	Exon 1 of 1	NP_005314.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
H1-6	ENST00000338379.6	TSL:6 MANE Select	c.40G>C	p.Val14Leu	missense	Exon 1 of 1	ENSP00000341214.5	P22492
H2BC4	ENST00000957524.1		c.*9+15461G>C		intron	N/A	ENSP00000627583.1
H2BC4	ENST00000707188.1		n.*9+15461G>C		intron	N/A	ENSP00000516775.1	P62807

Frequencies

GnomAD3 genomes

AF:

0.474

AC:

72005

AN:

151994

Hom.:

17703

Cov.:

show subpopulations

Gnomad AFR

AF:

0.384

Gnomad AMI

AF:

0.696

Gnomad AMR

AF:

0.447

Gnomad ASJ

AF:

0.435

Gnomad EAS

AF:

0.276

Gnomad SAS

AF:

0.425

Gnomad FIN

AF:

0.548

Gnomad MID

AF:

0.411

Gnomad NFE

AF:

0.542

Gnomad OTH

AF:

0.419

GnomAD2 exomes

AF:

0.481

AC:

120615

AN:

250620

AF XY:

0.480

show subpopulations

Gnomad AFR exome

AF:

0.383

Gnomad AMR exome

AF:

0.461

Gnomad ASJ exome

AF:

0.420

Gnomad EAS exome

AF:

0.274

Gnomad FIN exome

AF:

0.544

Gnomad NFE exome

AF:

0.545

Gnomad OTH exome

AF:

0.490

GnomAD4 exome

AF:

0.509

AC:

743509

AN:

1461426

Hom.:

192920

Cov.:

AF XY:

0.506

AC XY:

368115

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.377

AC:

12610

AN:

33470

American (AMR)

AF:

0.455

AC:

20353

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.421

AC:

11010

AN:

26134

East Asian (EAS)

AF:

0.198

AC:

7874

AN:

39688

South Asian (SAS)

AF:

0.417

AC:

35956

AN:

86234

European-Finnish (FIN)

AF:

0.544

AC:

28992

AN:

53318

Middle Eastern (MID)

AF:

0.379

AC:

2183

AN:

5754

European-Non Finnish (NFE)

AF:

0.535

AC:

594940

AN:

1111754

Other (OTH)

AF:

0.490

AC:

29591

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

20444

40888

61333

81777

102221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16702

33404

50106

66808

83510

<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:

0.474

AC:

72056

AN:

152112

Hom.:

17716

Cov.:

AF XY:

0.469

AC XY:

34895

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.384

AC:

15939

AN:

41488

American (AMR)

AF:

0.447

AC:

6828

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.435

AC:

1510

AN:

3468

East Asian (EAS)

AF:

0.277

AC:

1432

AN:

5178

South Asian (SAS)

AF:

0.425

AC:

2049

AN:

4824

European-Finnish (FIN)

AF:

0.548

AC:

5794

AN:

10566

Middle Eastern (MID)

AF:

0.422

AC:

124

AN:

294

European-Non Finnish (NFE)

AF:

0.542

AC:

36851

AN:

67988

Other (OTH)

AF:

0.424

AC:

894

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1918

3836

5753

7671

9589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

654

1308

1962

2616

3270

<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:

0.493

Hom.:

10955

Bravo

AF:

0.461

TwinsUK

AF:

0.518

AC:

1919

ALSPAC

AF:

0.531

AC:

2048

ESP6500AA

AF:

0.393

AC:

1733

ESP6500EA

AF:

0.530

AC:

4554

ExAC

AF:

0.484

AC:

58787

Asia WGS

AF:

0.409

AC:

1421

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.11

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.071

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0034

LIST_S2

Benign

0.19

MetaRNN

Benign

0.000024

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.0

PhyloP100

-1.6

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.20

REVEL

Benign

0.041

Sift

Benign

1.0

Sift4G

Benign

0.34

Polyphen

0.0

Vest4

0.041

MutPred

0.058

Loss of catalytic residue at V14 (P = 0.0217)

ClinPred

0.0022

GERP RS

-0.59

PromoterAI

0.031

Neutral

(source)

Varity_R

0.026

gMVP

0.30

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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