chr1-226064454-G-A

Position:

• chr1-226064454-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1 PM1 PM2 PM5 PP2

The NM_002107.7(H3-3A):​c.103G>A​(p.Gly35Arg) 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 other (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G35V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: H3-3A NM_002107.7 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 9.99

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 (HGNC:):

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 Lovd
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
H3-3A	NM_002107.7	c.103G>A	p.Gly35Arg	missense_variant	2/4	ENST00000366815.10	NP_002098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
H3-3A	ENST00000366815.10	c.103G>A	p.Gly35Arg	missense_variant	2/4	1	NM_002107.7	ENSP00000355780.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Glioblastoma Other:1

other, no assertion criteria provided

clinical testing

Donald Williams Parsons Laboratory, Baylor College of Medicine

May 01, 2016

- 3: Mutations in other consensus cancer genes, not currently considered targetable

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;T;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;.;D;.
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.4	M;M;.;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.4	D;D;D;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	.;.;D;.
Sift4G	Benign	0.070	T;T;T;T
Polyphen		0.95	P;P;P;P
Vest4		0.65
MutPred		0.32		Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);
MVP		0.67
MPC		2.2
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs1553260624; hg19: chr1-226252155; COSMIC: COSV64731793; COSMIC: COSV64731793;