17-75779056-T-C

Variant names:

• chr17-75779056-T-C
• rs1555585486
• NM_005324.5:c.119A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_005324.5(H3-3B):​c.119A>G​(p.His40Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: H3-3B NM_005324.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.62

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_pathogenic. Variant got 6 ACMG points.

• PM1: In a region_of_interest Disordered (size 42) in uniprot entity H33_HUMAN there are 23 pathogenic changes around while only 0 benign (100%) in NM_005324.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765
• PP5: Variant 17-75779056-T-C is Pathogenic according to our data. Variant chr17-75779056-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521569.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H3-3B	NM_005324.5	c.119A>G	p.His40Arg	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.119A>G	p.His40Arg	missense_variant	Exon 2 of 4	1	NM_005324.5	ENSP00000254810.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bryant-Li-Bhoj neurodevelopmental syndrome 2 Pathogenic:1

Jun 21, 2024

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The H3-3B c.119A>G p.(His40Arg) missense variant has been reported in a de novo state in an individual with Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB). Additionally, a different amino acid substitution at the same codon in the H3-3A gene, which encodes an identical protein as H3-3B, has also been reported in a de novo state in an individual with BRYLIB (PMID: 33268356). This region is a hot spot in both the H3-3B and H3-3A genes (PMID: 33268356; 34876591). This variant is not observed in version 2.1.1 or version 4.1.0 of the Genome Aggregation Database. Based on the available evidence, the c.119A>G p.(His40Arg) variant is classified as likely pathogenic for Bryant-Li-Bhoj neurodevelopmental syndrome. -

not provided Pathogenic:1

Nov 25, 2024

GeneDx

Significance: Likely pathogenic

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; This variant is associated with the following publications: (PMID: 33268356, 27535533) -

Inborn genetic diseases Uncertain:1

May 10, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Benign	0.90
DEOGEN2	Benign	0.086	.;T;.;.;.;.;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;D;.;.;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.93	T
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.6	D;.;.;.;.;.;.;.
REVEL	Uncertain	0.40
Sift4G	Benign	0.26	T;T;T;T;T;T;T;.
Vest4		0.62
MutPred		0.47		Gain of glycosylation at K37 (P = 0.0842);Gain of glycosylation at K37 (P = 0.0842);Gain of glycosylation at K37 (P = 0.0842);Gain of glycosylation at K37 (P = 0.0842);Gain of glycosylation at K37 (P = 0.0842);Gain of glycosylation at K37 (P = 0.0842);Gain of glycosylation at K37 (P = 0.0842);Gain of glycosylation at K37 (P = 0.0842);
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.8
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

Publications

LitVar

Other links and lift over

dbSNP: rs1555585486; hg19: chr17-73775137; COSMIC: COSV99637980; COSMIC: COSV99637980;