Genetic Variant H1-6:p.Val14Leu (chr6-26108054-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -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. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H1-6	NM_005323.4 link	c.40G>C	p.Val14Leu	missense_variant	Exon 1 of 1	ENST00000338379.6	NP_005314.2	P22492

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H1-6	ENST00000338379.6 link	c.40G>C	p.Val14Leu	missense_variant	Exon 1 of 1	6	NM_005323.4	ENSP00000341214.5		P22492
H2BC4	ENST00000707188.1 link	n.*9+15461G>C		intron_variant	Intron 1 of 2			ENSP00000516775.1

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

GnomAD3 exomes

AF:

0.481

AC:

120615

AN:

250620

Hom.:

30022

AF XY:

0.480

AC XY:

64997

AN XY:

135504

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 SAS exome

AF:

0.419

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

Gnomad4 AFR exome

AF:

0.377

Gnomad4 AMR exome

AF:

0.455

Gnomad4 ASJ exome

AF:

0.421

Gnomad4 EAS exome

AF:

0.198

Gnomad4 SAS exome

AF:

0.417

Gnomad4 FIN exome

AF:

0.544

Gnomad4 NFE exome

AF:

0.535

Gnomad4 OTH exome

AF:

0.490

GnomAD4 genome

AF:

0.474

AC:

72056

AN:

152112

Hom.:

17716

Cov.:

AF XY:

0.469

AC XY:

34895

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.384

Gnomad4 AMR

AF:

0.447

Gnomad4 ASJ

AF:

0.435

Gnomad4 EAS

AF:

0.277

Gnomad4 SAS

AF:

0.425

Gnomad4 FIN

AF:

0.548

Gnomad4 NFE

AF:

0.542

Gnomad4 OTH

AF:

0.424

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.11

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

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

Varity_R

0.026

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over