Genetic Variant H4C12:p.Ala16Ala (chr6-27831480-A-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003541.3(H4C12):c.48T>A(p.Ala16Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0419 in 1,526,882 control chromosomes in the GnomAD database, including 1,248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 112 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1136 hom. )

Consequence

H4C12
NM_003541.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.439

Variant links:

Genes affected

H4C12 (HGNC:4784): (H4 clustered histone 12) 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 small histone gene cluster on chromosome 6p22-p21.3. [provided by RefSeq, Aug 2015]

H4C12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 6-27831480-A-T is Benign according to our data. Variant chr6-27831480-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 774643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.439 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H4C12	NM_003541.3 link	c.48T>A	p.Ala16Ala	synonymous_variant	Exon 1 of 1	ENST00000611927.2	NP_003532.1	P62805B2R4R0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H4C12	ENST00000611927.2 link	c.48T>A	p.Ala16Ala	synonymous_variant	Exon 1 of 1	6	NM_003541.3	ENSP00000479794.2		P62805

Frequencies

GnomAD3 genomes

AF:

0.0335

AC:

5101

AN:

152178

Hom.:

113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00794

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.0201

Gnomad ASJ

AF:

0.0268

Gnomad EAS

AF:

0.0221

Gnomad SAS

AF:

0.0702

Gnomad FIN

AF:

0.0624

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0462

Gnomad OTH

AF:

0.0297

GnomAD3 exomes

AF:

0.0394

AC:

6684

AN:

169720

Hom.:

188

AF XY:

0.0418

AC XY:

3772

AN XY:

90168

show subpopulations

Gnomad AFR exome

AF:

0.00669

Gnomad AMR exome

AF:

0.0154

Gnomad ASJ exome

AF:

0.0274

Gnomad EAS exome

AF:

0.0184

Gnomad SAS exome

AF:

0.0771

Gnomad FIN exome

AF:

0.0645

Gnomad NFE exome

AF:

0.0437

Gnomad OTH exome

AF:

0.0404

GnomAD4 exome

AF:

0.0429

AC:

58945

AN:

1374586

Hom.:

1136

Cov.:

AF XY:

0.0440

AC XY:

29713

AN XY:

675500

show subpopulations

Gnomad4 AFR exome

AF:

0.00557

Gnomad4 AMR exome

AF:

0.0160

Gnomad4 ASJ exome

AF:

0.0273

Gnomad4 EAS exome

AF:

0.00899

Gnomad4 SAS exome

AF:

0.0755

Gnomad4 FIN exome

AF:

0.0654

Gnomad4 NFE exome

AF:

0.0433

Gnomad4 OTH exome

AF:

0.0389

GnomAD4 genome

AF:

0.0335

AC:

5096

AN:

152296

Hom.:

112

Cov.:

AF XY:

0.0346

AC XY:

2573

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00791

Gnomad4 AMR

AF:

0.0201

Gnomad4 ASJ

AF:

0.0268

Gnomad4 EAS

AF:

0.0214

Gnomad4 SAS

AF:

0.0702

Gnomad4 FIN

AF:

0.0624

Gnomad4 NFE

AF:

0.0462

Gnomad4 OTH

AF:

0.0294

Alfa

AF:

0.0370

Hom.:

Bravo

AF:

0.0279

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 23, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

5.1

DANN

Benign

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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