Genetic Variant H3-3B:p.Ile90Ile (chr17-75778822-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

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

The NM_005324.5(H3-3B):c.270C>T(p.Ile90Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,614,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

H3-3B
NM_005324.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0480

Variant links:

Genes affected

H3-3B (HGNC:4765): (H3.3 histone B) 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 contains introns and its mRNA is polyadenylated, unlike most histone genes. The protein encoded by this gene is a replication-independent histone that is a member of the histone H3 family. Pseudogenes of this gene have been identified on the X chromosome, and on chromosomes 5, 13 and 17. [provided by RefSeq, Oct 2015]

H3-3B 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=-0.79).

BP6

Variant 17-75778822-G-A is Benign according to our data. Variant chr17-75778822-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3771757.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.048 with no splicing effect.

BS2

High AC in GnomAdExome4 at 83 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H3-3B	NM_005324.5 link	c.270C>T	p.Ile90Ile	synonymous_variant	Exon 3 of 4	ENST00000254810.8	NP_005315.1	P84243B2R4P9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H3-3B	ENST00000254810.8 link	c.270C>T	p.Ile90Ile	synonymous_variant	Exon 3 of 4	1	NM_005324.5	ENSP00000254810.3		P84243

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000294

AC:

AN:

251388

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00214

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00177

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000147

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

H3-3B: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

4.6

DANN

Benign

0.92

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over