1-226065664-C-T

Variant names:

• chr1-226065664-C-T
• rs1657901999
• NM_002107.7:c.137C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The NM_002107.7(H3-3A):​c.137C>T​(p.Thr46Ile) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T46N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: H3-3A NM_002107.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.91
• 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

ACMG classification

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

• PM1: In a chain Histone H3.3 (size 134) in uniprot entity H33_HUMAN there are 22 pathogenic changes around while only 1 benign (96%) 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.
• PP5: Variant 1-226065664-C-T is Pathogenic according to our data. Variant chr1-226065664-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 985335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.137C>T	p.Thr46Ile	missense	Exon 3 of 4	NP_002098.1	P84243
	H3-3A	NM_001379043.1		c.137C>T	p.Thr46Ile	missense	Exon 4 of 5	NP_001365972.1	P84243
	H3-3A	NM_001379045.1		c.137C>T	p.Thr46Ile	missense	Exon 4 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.137C>T	p.Thr46Ile	missense	Exon 3 of 4	ENSP00000355780.3	P84243
	H3-3A	ENST00000366813.1	TSL:1	c.137C>T	p.Thr46Ile	missense	Exon 2 of 3	ENSP00000355778.1	P84243
	H3-3A	ENST00000921925.1		c.137C>T	p.Thr46Ile	missense	Exon 3 of 4	ENSP00000591984.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Bryant-Li-Bhoj neurodevelopmental syndrome 1 (3)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Benign	0.94
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.032	D
Polyphen		0.21	B
Vest4		0.75
MutPred		0.31		Loss of phosphorylation at T46 (P = 0.0205)
MVP		0.76
MPC		2.1
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.90
gMVP		0.97
Mutation Taster		=31/69	disease causing (ClinVar)

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

dbSNP: rs1657901999; hg19: chr1-226253365;