chr1-226064419-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PM1 PM2 PP2 PP3 PP5_Very_Strong 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: H3-3A NM_002107.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 7.90
• Publications: 0 publications found

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]

H3-3A Gene-Disease associations (from GenCC):

• Bryant-Li-Bhoj neurodevelopmental syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Illumina

ENSG00000299101 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_002107.7
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. 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). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Bryant-Li-Bhoj neurodevelopmental syndrome 1.
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN [when BayesDel_noAF, max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 1-226064419-C-T is Pathogenic according to our data. Variant chr1-226064419-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3343880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.4207675). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002107.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H3-3A	NM_002107.7	MANE Select	c.68C>T	p.Thr23Ile	missense	Exon 2 of 4	NP_002098.1	P84243
	H3-3A	NM_001379043.1		c.68C>T	p.Thr23Ile	missense	Exon 3 of 5	NP_001365972.1	P84243
	H3-3A	NM_001379045.1		c.68C>T	p.Thr23Ile	missense	Exon 3 of 5	NP_001365974.1	P84243

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H3-3A	ENST00000366815.10	TSL:1 MANE Select	c.68C>T	p.Thr23Ile	missense	Exon 2 of 4	ENSP00000355780.3	P84243
	H3-3A	ENST00000366813.1	TSL:1	c.68C>T	p.Thr23Ile	missense	Exon 1 of 3	ENSP00000355778.1	P84243
	H3-3A	ENST00000921925.1		c.68C>T	p.Thr23Ile	missense	Exon 2 of 4	ENSP00000591984.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Bryant-Li-Bhoj neurodevelopmental syndrome 1 (1)
-	1	-	H3-3A-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	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
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.22		Loss of glycosylation at T23 (P = 0.0096)
MVP		0.68
MPC		3.5
ClinPred		1.0	D
GERP RS		4.3
PromoterAI		0.051	Neutral
Varity_R		0.94
gMVP		0.77
Mutation Taster		=42/58	disease causing

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

Other links and lift over

hg19: chr1-226252120;