rs1276519904

Positions:

• chr1-226071445-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The NM_002107.7(H3-3A):​c.377A>G​(p.Gln126Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000984 in 1,016,260 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 9.8e-7 (0 hom.)
• Consequence: H3-3A NM_002107.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.22

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 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.
• PP5: Variant 1-226071445-A-G is Pathogenic according to our data. Variant chr1-226071445-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
H3-3A	NM_002107.7	c.377A>G	p.Gln126Arg	missense_variant	4/4	ENST00000366815.10	NP_002098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
H3-3A	ENST00000366815.10	c.377A>G	p.Gln126Arg	missense_variant	4/4	1	NM_002107.7	ENSP00000355780.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 9.84e-7 AC: 1 AN: 1016260 Hom.: 0 Cov.: 13 AF XY: 0.00000191 AC XY: 1 AN XY: 524122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000131

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bryant-Li-Bhoj neurodevelopmental syndrome 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 24, 2023	The H3-3A (also referred to as H3F3A) c.377A>G (p.Gln126Arg) missense variant results in the substitution of glutamine at amino acid position 126 with arginine. This variant has been reported in a de novo state in at least three unrelated individuals with developmental delay, seizures, variable brain anomalies and dysmorphisms among other features (PMID: 33268356). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. De novo missense variants are reported as a common mechanism of disease, and this variant was identified in a de novo state. Based on the available evidence, the c.377A>G (p.Gln126Arg) variant is classified as pathogenic for Bryant-Li-Bhoj neurodevelopmental syndrome. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2015

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2018

- -

H3F3A-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Nov 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.048	T;T;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.5	M;M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.52
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.023	B;B;B
Vest4		0.86
MutPred		0.65		Gain of MoRF binding (P = 0.0523);Gain of MoRF binding (P = 0.0523);Gain of MoRF binding (P = 0.0523);
MVP		1.0
MPC		2.1
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.87
gMVP		0.99

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: rs1276519904; hg19: chr1-226259146;