1-226065664-C-A

Position:

• chr1-226065664-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_002107.7(H3-3A):​c.137C>A​(p.Thr46Asn) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T46I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: H3-3A NM_002107.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 7 ACMG points.

• PM1: In a chain Histone H3.3 (size 134) in uniprot entity H33_HUMAN there are 31 pathogenic changes around while only 0 benign (100%) in NM_002107.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-226065664-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 985335.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, H3-3A

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
H3-3A	NM_002107.7	c.137C>A	p.Thr46Asn	missense_variant	3/4	ENST00000366815.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
H3-3A	ENST00000366815.10	c.137C>A	p.Thr46Asn	missense_variant	3/4	1	NM_002107.7	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bryant-Li-Bhoj neurodevelopmental syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3billion

Feb 23, 2023

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.74). A different missense change at the same codon (p.Thr46Ile) has been reported to be associated with H3-3A related disorder (ClinVar ID: VCV000985335 / PMID: 33268356). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	31
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T;T;T;T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Pathogenic	4.6	H;H;.;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.9	D;D;D;D
REVEL	Uncertain	0.44
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.85	P;P;D;P
Vest4		0.80
MutPred		0.24		Loss of phosphorylation at T46 (P = 0.0205);Loss of phosphorylation at T46 (P = 0.0205);Loss of phosphorylation at T46 (P = 0.0205);Loss of phosphorylation at T46 (P = 0.0205);
MVP		0.76
MPC		3.4
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.97

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: chr1-226253365;