NM_002107.7:c.68C>T

Variant names:

• chr1-226064419-C-T
• NM_002107.7:c.68C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PP2 PP5_Moderate BP4

The NM_002107.7(H3-3A):​c.68C>T​(p.Thr23Ile) 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 benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: H3-3A NM_002107.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.90

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 6 ACMG points.

• PM1: In a region_of_interest Disordered (size 42) in uniprot entity H33_HUMAN there are 16 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 the H3-3A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.1568 (above the threshold of 3.09). GenCC associations: The gene is linked to Bryant-Li-Bhoj neurodevelopmental syndrome 1.
• PP5: Variant 1-226064419-C-T is Pathogenic according to our data. Variant chr1-226064419-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3343880.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.4207675). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H3-3A	NM_002107.7	c.68C>T	p.Thr23Ile	missense_variant	Exon 2 of 4	ENST00000366815.10	NP_002098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H3-3A	ENST00000366815.10	c.68C>T	p.Thr23Ile	missense_variant	Exon 2 of 4	1	NM_002107.7	ENSP00000355780.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Feb 02, 2024

GeneDx

Significance: 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, 35599849) -

H3-3A-related disorder Uncertain:1

Apr 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The H3-3A c.68C>T variant is predicted to result in the amino acid substitution p.Thr23Ile. This variant was reported in at least two individuals with Neurodegenerative disease and in at least one individual was this variant observed de novo (Figure 1 as T22I, Bryant et al 2020. PubMed ID: 33268356; Table 1, Elliott et al. 2022. PubMed ID: 35599849). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect 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	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T;T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	.;.;D;.
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	3.0	M;M;.;M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.1	D;D;D;D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	.;.;D;.
Sift4G	Uncertain	0.043	D;D;T;D
Polyphen		1.0	D;D;D;D
Vest4		0.49
MutPred		0.22		Loss of glycosylation at T23 (P = 0.0096);Loss of glycosylation at T23 (P = 0.0096);Loss of glycosylation at T23 (P = 0.0096);Loss of glycosylation at T23 (P = 0.0096);
MVP		0.68
MPC		3.5
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.94
gMVP		0.77

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: chr1-226252120;