chr1-226065658-C-T

Position:

• chr1-226065658-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_002107.7(H3-3A):​c.131C>T​(p.Pro44Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

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

H3-3A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
H3-3A	NM_002107.7	c.131C>T	p.Pro44Leu	missense_variant, splice_region_variant	3/4	ENST00000366815.10	NP_002098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
H3-3A	ENST00000366815.10	c.131C>T	p.Pro44Leu	missense_variant, splice_region_variant	3/4	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

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	29
DANN	Benign	0.96
DEOGEN2	Benign	0.32	T;T;T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	.;.;D;.
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	3.2	M;M;.;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-9.7	D;D;D;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	.;.;D;.
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		0.50	P;P;B;P
Vest4		0.74
MutPred		0.27		Loss of glycosylation at P44 (P = 0.0412);Loss of glycosylation at P44 (P = 0.0412);Loss of glycosylation at P44 (P = 0.0412);Loss of glycosylation at P44 (P = 0.0412);
MVP		0.82
MPC		3.0
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.92
gMVP		0.94

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: rs1657901897; hg19: chr1-226253359;