chr1-226064403-A-G

Position:

• chr1-226064403-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PS1_Moderate PM1 PM2 PP2 PP5_Moderate BP4

The NM_002107.7(H3-3A):​c.52A>G​(p.Arg18Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 31)
• Consequence: H3-3A NM_002107.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.51

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PS1: Transcript NM_002107.7 (H3-3A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a region_of_interest Disordered (size 42) in uniprot entity H33_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) 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 1-226064403-A-G is Pathogenic according to our data. Variant chr1-226064403-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1339283.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.4142698). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
H3-3A	NM_002107.7	c.52A>G	p.Arg18Gly	missense_variant	2/4	ENST00000366815.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
H3-3A	ENST00000366815.10	c.52A>G	p.Arg18Gly	missense_variant	2/4	1	NM_002107.7	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). ClinVar contains an entry for this variant (Variation ID: 1339283). This variant is also known as p.R17G. This missense change has been observed in individual(s) with Bryant-Li-Bhoj neurodevelopmental syndrome (PMID: 33268356). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 18 of the H3F3A protein (p.Arg18Gly). -

Bryant-Li-Bhoj neurodevelopmental syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Benign	0.89
DEOGEN2	Benign	0.15	T;T;T;T
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.94	.;.;D;.
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	3.1	M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.8	D;D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0070	.;.;D;.
Sift4G	Benign	0.076	T;T;T;T
Polyphen		0.0090	B;B;D;B
Vest4		0.71
MutPred		0.28		Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);
MVP		0.87
MPC		2.6
ClinPred		0.95	D
GERP RS		3.1
Varity_R		0.99
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-226252104; COSMIC: COSV100831279; COSMIC: COSV100831279;