dbSNP rs1057519903: H3-3A:p.Lys28Arg (chr1-226064434-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate

The NM_002107.7(H3-3A):c.83A>G(p.Lys28Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K28M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

H3-3A
NM_002107.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.32

Publications

0 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: Illumina, ClinGen, G2P

H3-3A links:

ENSG00000299101 (HGNC:):

ENSG00000299101 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 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, 4 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.25037754).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
H3-3A	NM_002107.7	MANE Select	c.83A>G	p.Lys28Arg	missense	Exon 2 of 4	NP_002098.1	P84243
H3-3A	NM_001379043.1		c.83A>G	p.Lys28Arg	missense	Exon 3 of 5	NP_001365972.1	P84243
H3-3A	NM_001379045.1		c.83A>G	p.Lys28Arg	missense	Exon 3 of 5	NP_001365974.1	P84243

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
H3-3A	ENST00000366815.10	TSL:1 MANE Select	c.83A>G	p.Lys28Arg	missense	Exon 2 of 4	ENSP00000355780.3	P84243
H3-3A	ENST00000366813.1	TSL:1	c.83A>G	p.Lys28Arg	missense	Exon 1 of 3	ENSP00000355778.1	P84243
H3-3A	ENST00000921925.1		c.83A>G	p.Lys28Arg	missense	Exon 2 of 4	ENSP00000591984.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.023

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.035

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.6

PhyloP100

9.3

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.25

Sift

Uncertain

0.0070

Sift4G

Benign

0.098

Polyphen

0.0030

Vest4

0.42

MutPred

0.24

Loss of ubiquitination at K28 (P = 0.0381)

MVP

0.82

MPC

1.8

ClinPred

0.96

GERP RS

4.3

PromoterAI

-0.074

Neutral

(source)

Varity_R

0.97

gMVP

0.78

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over