1-226065771-G-C

Position:

• chr1-226065771-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_002107.7(H3-3A):​c.244G>C​(p.Asp82His) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D82G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: H3-3A NM_002107.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.98

Genes affected

H3-3A (HGNC:4764): (H3.3 histone A) 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 is a replication-independent member of the histone H3 family. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a chain Histone H3.3 (size 134) in uniprot entity H33_HUMAN there are 34 pathogenic changes around while only 0 benign (100%) in NM_002107.7
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), H3-3A. . Gene score misZ 3.1568 (greater than the threshold 3.09). GenCC has associacion of gene with Bryant-Li-Bhoj neurodevelopmental syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87
• PP5: Variant 1-226065771-G-C is Pathogenic according to our data. Variant chr1-226065771-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 985323.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
H3-3A	NM_002107.7	c.244G>C	p.Asp82His	missense_variant	3/4	ENST00000366815.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
H3-3A	ENST00000366815.10	c.244G>C	p.Asp82His	missense_variant	3/4	1	NM_002107.7	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2018

- -

H3-3A-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 2024

The H3-3A c.244G>C variant is predicted to result in the amino acid substitution p.Asp82His. This variant was reported as heterozygous in several individuals with developmental disorder (McRae et al. 2017. PubMed ID: 28135719, Table S1; Turner et al. 2019. PubMed ID: 31785789, Table S2; Bryant et al. 2020. PubMed ID: 33268356, Table S1). This variant has not been reported in a large population database, indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T;T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	.;.;D;.
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Pathogenic	3.0	M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.4	D;D;D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	.;.;D;.
Sift4G	Uncertain	0.028	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.91
MutPred		0.55		Gain of MoRF binding (P = 0.0381);Gain of MoRF binding (P = 0.0381);Gain of MoRF binding (P = 0.0381);Gain of MoRF binding (P = 0.0381);
MVP		0.91
MPC		4.0
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.96

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: rs1657903750; hg19: chr1-226253472;