rs1276519904
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PP2PP5_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. 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
NM_002107.7 missense
Scores
4
6
6
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM1
?
In a helix (size 9) in uniprot entity H33_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_002107.7
PP2
?
Missense variant where missense usually causes diseases, H3-3A
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 | UniProt |
---|---|---|---|---|---|---|---|
H3-3A | NM_002107.7 | c.377A>G | p.Gln126Arg | missense_variant | 4/4 | ENST00000366815.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
H3-3A | ENST00000366815.10 | c.377A>G | p.Gln126Arg | missense_variant | 4/4 | 1 | NM_002107.7 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 genomes
?
Cov.:
30
GnomAD4 exome AF: 9.84e-7 AC: 1AN: 1016260Hom.: 0 Cov.: 13 AF XY: 0.00000191 AC XY: 1AN XY: 524122
GnomAD4 exome
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1
AN:
1016260
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13
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AC XY:
1
AN XY:
524122
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GnomAD4 genome ? Cov.: 30
GnomAD4 genome
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Cov.:
30
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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 condition Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Nov 03, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Benign
DEOGEN2
Benign
T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift4G
Uncertain
D;D;D
Polyphen
B;B;B
Vest4
MutPred
Gain of MoRF binding (P = 0.0523);Gain of MoRF binding (P = 0.0523);Gain of MoRF binding (P = 0.0523);
MVP
MPC
2.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at