17-75778652-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_005324.5(H3-3B):c.354C>A(p.Val118=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: H3-3B NM_005324.5 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.22694).
• BP7: Synonymous conserved (PhyloP=3.51 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
H3-3B	NM_005324.5	c.354C>A	p.Val118=	synonymous_variant	4/4	ENST00000254810.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
H3-3B	ENST00000254810.8	c.354C>A	p.Val118=	synonymous_variant	4/4	1	NM_005324.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hemiparkinsonism-hemiatrophy syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Nov 16, 2020

The heterozygous p.Ser147Ter variant in H3F3B was identified by our study in 1 individual with hemiparkinsonism. Trio genome analysis showed this variant to be de novo. The variant has not been previously reported in individuals with hemiparkinsonism and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 147. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. It is of note that loss of function of H3F3B in an autosomal dominant disease has not yet been established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). Finally, although this gene has been reported in association with hemiparkinsonism, it currently has limited evidence for these associations. In summary, while there is some suspicion for a pathogenic role, the evidence for this gene-disease relationship is limited and therefore the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS2, PM2 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	13
Dann	Benign	0.90
FATHMM_MKL	Uncertain	0.82	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
Vest4		0.39
GERP RS		3.2

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: rs766432479; hg19: chr17-73774733;