rs1555585522

Variant names:

• chr17-75779152-G-A
• rs1555585522
• NM_005324.5:c.23C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The NM_005324.5(H3-3B):​c.23C>T​(p.Ala8Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: H3-3B NM_005324.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 9.49
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Bryant-Li-Bhoj neurodevelopmental syndrome 2

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain in NM_005324.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the H3-3B gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.8781 (below the threshold of 3.09). Trascript score misZ: 4.0007 (above the threshold of 3.09). GenCC associations: The gene is linked to Bryant-Li-Bhoj neurodevelopmental syndrome 2.
• PP5: Variant 17-75779152-G-A is Pathogenic according to our data. Variant chr17-75779152-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521247.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H3-3B	NM_005324.5	c.23C>T	p.Ala8Val	missense_variant	Exon 2 of 4	ENST00000254810.8	NP_005315.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H3-3B	ENST00000254810.8	c.23C>T	p.Ala8Val	missense_variant	Exon 2 of 4	1	NM_005324.5	ENSP00000254810.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bryant-Li-Bhoj neurodevelopmental syndrome 2 Pathogenic:1

Nov 19, 2022

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Jun 09, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.23C>T (p.A8V) alteration is located in exon 2 (coding exon 1) of the H3F3B gene. This alteration results from a C to T substitution at nucleotide position 23, causing the alanine (A) at amino acid position 8 to be replaced by a valine (V). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported de novo in an individual with features consistent with H3-3-related neurodevelopmental disorder (Okur, 2021). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional analysis to determine protein level was performed using HEK293T cells transiently transfected with the p.A8V alteration. The results did not show significantly altered protein level compared to the wild type (Okur, 2021). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Short stature;C0454644:Delayed speech and language development;C0557874:Global developmental delay;C2711610:Brain imaging abnormality;C3714756:Intellectual disability Pathogenic:1

Jul 15, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Uncertain:1

Jun 02, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.082	.;T;.;.;.;.;T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	.;D;D;.;.;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
PhyloP100		9.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.8	D;.;.;.;.;.;.;.
REVEL	Uncertain	0.33
Sift4G	Uncertain	0.049	D;T;D;D;D;D;D;.
Vest4		0.89
MutPred		0.33		Loss of phosphorylation at T4 (P = 0.1721);Loss of phosphorylation at T4 (P = 0.1721);Loss of phosphorylation at T4 (P = 0.1721);Loss of phosphorylation at T4 (P = 0.1721);Loss of phosphorylation at T4 (P = 0.1721);Loss of phosphorylation at T4 (P = 0.1721);Loss of phosphorylation at T4 (P = 0.1721);Loss of phosphorylation at T4 (P = 0.1721);
MVP		0.97
MPC		1.8
ClinPred		0.99	D
GERP RS		5.1
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.85

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

Other links and lift over

dbSNP: rs1555585522; hg19: chr17-73775233;