1-226064376-C-G

Position:

• chr1-226064376-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_Moderate PM1 PM2 PM5 PP2 PP5_Moderate

The NM_002107.7(H3-3A):​c.25C>G​(p.Arg9Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R9S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: H3-3A NM_002107.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.84

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 Pathogenic. Variant got 11 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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 1-226064376-C-G is Pathogenic according to our data. Variant chr1-226064376-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3103884.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
H3-3A	NM_002107.7	c.25C>G	p.Arg9Gly	missense_variant	2/4	ENST00000366815.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
H3-3A	ENST00000366815.10	c.25C>G	p.Arg9Gly	missense_variant	2/4	1	NM_002107.7	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 24, 2021

The c.25C>G (p.R9G) alteration is located in exon 2 (coding exon 1) of the H3-3A gene. This alteration results from a C to G substitution at nucleotide position 25, causing the arginine (R) at amino acid position 9 to be replaced by a glycine (G). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported de novo in a male infant who was small for gestational age and had malformation of the corpus callosum, relative macrocephaly, refractory seizures, generalized hypotonia, roving eye movements, clubfoot, dysmorphic features, and possible hearing loss. The patient died at 2 months of age. In addition, two other alterations affecting the same codon in H3-3A, p.R9S, and in H3-3B, p.R9C, were reported de novo in patients with global developmental delay and congenital anomalies (Bryant, 2020). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T;T;T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	.;.;T;.
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.4	M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.2	D;D;D;D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	.;.;D;.
Sift4G	Benign	0.062	T;T;D;T
Polyphen		0.0010	B;B;D;B
Vest4		0.75
MutPred		0.33		Loss of stability (P = 0.0422);Loss of stability (P = 0.0422);Loss of stability (P = 0.0422);Loss of stability (P = 0.0422);
MVP		0.73
MPC		2.3
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.99
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr1-226252077; COSMIC: COSV64733215; COSMIC: COSV64733215;