1-226065712-T-G

Variant names:

• chr1-226065712-T-G
• rs1657902836
• NM_002107.7:c.185T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_002107.7(H3-3A):​c.185T>G​(p.Leu62Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: H3-3A NM_002107.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 9 ACMG points.

• PM1: In a chain Histone H3.3 (size 134) in uniprot entity H33_HUMAN there are 35 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 the H3-3A gene, where missense mutations are typically associated with disease (based on misZ statistic). 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). GenCC associations: The gene is linked to Bryant-Li-Bhoj neurodevelopmental syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H3-3A	NM_002107.7	c.185T>G	p.Leu62Arg	missense_variant	Exon 3 of 4	ENST00000366815.10	NP_002098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H3-3A	ENST00000366815.10	c.185T>G	p.Leu62Arg	missense_variant	Exon 3 of 4	1	NM_002107.7	ENSP00000355780.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 11, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PS2_M,PM2,PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;T;T;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	.;.;D;.
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	5.0	H;H;.;H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.7	D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;.;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.97
MutPred		0.80		Gain of disorder (P = 0.0142);Gain of disorder (P = 0.0142);Gain of disorder (P = 0.0142);Gain of disorder (P = 0.0142);
MVP		0.97
MPC		4.9
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.99
gMVP		1.0

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: rs1657902836; hg19: chr1-226253413;