17-75778629-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_005324.5(H3-3B):c.377A>G(p.Gln126Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q126K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: H3-3B NM_005324.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.13

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a helix (size 9) in uniprot entity H33_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005324.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-75778630-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2573076.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, H3-3B
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783
• PP5: Variant 17-75778629-T-C is Pathogenic according to our data. Variant chr17-75778629-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1339275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
H3-3B	NM_005324.5	c.377A>G	p.Gln126Arg	missense_variant	4/4	ENST00000254810.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
H3-3B	ENST00000254810.8	c.377A>G	p.Gln126Arg	missense_variant	4/4	1	NM_005324.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bryant-Li-Bhoj neurodevelopmental syndrome 2 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	Mar 03, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 02, 2022	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Medical Genetics, University of Torino	Nov 29, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.72; 3Cnet: 3CNET). The variant has been previously reported as de novo in a similarly affected individual (PMID: 33268356). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

H3-3B-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2023

The H3-3B c.377A>G variant is predicted to result in the amino acid substitution p.Gln126Arg. This variant was reported as de novo in a patient with neurodegenerative disease with features of developmental delay, brain abnormalities, seizures, hypotonia, strabismus, hypertelorism and constipation (Table S1, Bryant. 2020. PubMed ID: 33268356). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Uncertain	25
Dann	Benign	0.92
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.2	N;.;.;.;.
REVEL	Pathogenic	0.72
Sift4G	Uncertain	0.014	D;D;D;D;D
Vest4		0.51
MutPred		0.55		Gain of MoRF binding (P = 0.0523);Gain of MoRF binding (P = 0.0523);Gain of MoRF binding (P = 0.0523);Gain of MoRF binding (P = 0.0523);Gain of MoRF binding (P = 0.0523);
MVP		1.0
MPC		2.0
ClinPred		0.86	D
GERP RS		5.3
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-73774710; COSMIC: COSV105037873; COSMIC: COSV105037873;