rs1276519904

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PP2PP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.22

Publications

1 publications found

Variant links:

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: G2P, Illumina, ClinGen

H3-3A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM1

In a hotspot region, there are 5 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.

PP5

Variant 1-226071445-A-G is Pathogenic according to our data. Variant chr1-226071445-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 520774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H3-3A	NM_002107.7 link	c.377A>G	p.Gln126Arg	missense_variant	Exon 4 of 4	ENST00000366815.10	NP_002098.1	P84243B2R4P9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H3-3A	ENST00000366815.10 link	c.377A>G	p.Gln126Arg	missense_variant	Exon 4 of 4	1	NM_002107.7	ENSP00000355780.3		P84243

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.84e-7

AC:

AN:

1016260

Hom.:

Cov.:

AF XY:

0.00000191

AC XY:

AN XY:

524122

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26192

American (AMR)

AF:

0.00

AC:

AN:

42332

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23278

East Asian (EAS)

AF:

0.00

AC:

AN:

37632

South Asian (SAS)

AF:

0.0000131

AC:

AN:

76344

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4782

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

719480

Other (OTH)

AF:

0.00

AC:

AN:

45802

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000843

Hom.:

Bravo

AF:

0.00000378

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

Feb 24, 2023

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 01, 2022

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inborn genetic diseases

Pathogenic:1

Sep 23, 2015

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Nov 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

H3F3A-related disorder

Pathogenic:1

Nov 03, 2017

Undiagnosed Diseases Network, NIH

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

(source)

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

M_CAP

Benign

0.066

MetaRNN

Uncertain

0.67

D;D;D

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.5

M;M;M

PhyloP100

9.2

PrimateAI

Pathogenic

0.87

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

GERP RS

5.8

Varity_R

0.87

gMVP

0.99

Mutation Taster

=39/61

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over