Genetic Variant H4C6:p.Val82Val (chr6-26240671-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_003540.4(H4C6):c.246C>T(p.Val82Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,612,128 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 3 hom. )

Consequence

H4C6
NM_003540.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.267

Variant links:

Genes affected

H4C6 (HGNC:4783): (H4 clustered histone 6) 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. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H4 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]

H4C6 links:

ENSG00000291336 (HGNC:):

ENSG00000291336 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 6-26240671-C-T is Benign according to our data. Variant chr6-26240671-C-T is described in ClinVar as [Benign]. Clinvar id is 719489.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.267 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H4C6	NM_003540.4 link	c.246C>T	p.Val82Val	synonymous_variant	Exon 1 of 1	ENST00000244537.6	NP_003531.1	P62805B2R4R0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
H4C6	ENST00000244537.6 link	c.246C>T	p.Val82Val	synonymous_variant	Exon 1 of 1	6	NM_003540.4	ENSP00000244537.6	P62805
ENSG00000291336	ENST00000707189.1 link	n.999+116500C>T		intron_variant	Intron 1 of 1
ENSG00000291338	ENST00000707191.1 link	n.1000+82550C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00179

AC:

272

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000426

AC:

106

AN:

248660

Hom.:

AF XY:

0.000320

AC XY:

AN XY:

134284

show subpopulations

Gnomad AFR exome

AF:

0.00493

Gnomad AMR exome

AF:

0.000464

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000991

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000447

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000177

AC:

258

AN:

1459770

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

107

AN XY:

726114

show subpopulations

Gnomad4 AFR exome

AF:

0.00502

Gnomad4 AMR exome

AF:

0.000493

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000931

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.000514

GnomAD4 genome

AF:

0.00180

AC:

275

AN:

152358

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

132

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00608

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000888

Hom.:

Bravo

AF:

0.00196

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 24, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

7.6

DANN

Benign

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over