6-26108054-C-G

Position:

• chr6-26108054-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.47 (17716 hom., cov: 32)
  • Exomes 𝑓: 0.51 (192920 hom.)
• Consequence: H1-6 NM_005323.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.62

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]

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]

ACMG classification

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/exons	MANE	Protein	UniProt
H1-6	NM_005323.4	c.40G>C	p.Val14Leu	missense_variant	1/1	ENST00000338379.6	NP_005314.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
H1-6	ENST00000338379.6	c.40G>C	p.Val14Leu	missense_variant	1/1		NM_005323.4	ENSP00000341214	P1
H2BC4	ENST00000707188.1	c.*9+15461G>C		intron_variant, NMD_transcript_variant				ENSP00000516775

Frequencies

GnomAD3 genomes AF: 0.474 AC: 72005 AN: 151994 Hom.: 17703 Cov.: 32

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

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.: 46 AF XY: 0.506 AC XY: 368115 AN XY: 726998

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.: 32 AF XY: 0.469 AC XY: 34895 AN XY: 74362

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	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.11
DANN	Benign	0.45
DEOGEN2	Benign	0.071	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.000024	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.041
Sift	Benign	1.0	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.041
MutPred		0.058		Loss of catalytic residue at V14 (P = 0.0217);
ClinPred		0.0022	T
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

Other links and lift over

dbSNP: rs198844; hg19: chr6-26108282; COSMIC: COSV58090341; COSMIC: COSV58090341;