chr1-226065670-C-T

Position:

• chr1-226065670-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.143C>T​(p.Ala48Val) 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: H3-3A NM_002107.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.91

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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	UniProt
H3-3A	NM_002107.7	c.143C>T	p.Ala48Val	missense_variant	3/4	ENST00000366815.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
H3-3A	ENST00000366815.10	c.143C>T	p.Ala48Val	missense_variant	3/4	1	NM_002107.7	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2023

The c.143C>T (p.A48V) alteration is located in exon 3 (coding exon 2) of the H3F3A gene. This alteration results from a C to T substitution at nucleotide position 143, causing the alanine (A) at amino acid position 48 to be replaced by a valine (V). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported de novo in an individual from a cohort of patients with autism spectrum disorder and/or developmental delay (Fu, 2022). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	.;.;T;.
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Pathogenic	3.7	H;H;.;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	.;.;D;.
Sift4G	Uncertain	0.030	D;D;D;D
Polyphen		0.97	D;D;D;D
Vest4		0.81
MutPred		0.33		Loss of disorder (P = 0.1023);Loss of disorder (P = 0.1023);Loss of disorder (P = 0.1023);Loss of disorder (P = 0.1023);
MVP		0.78
MPC		2.6
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-226253371; COSMIC: COSV64732350; COSMIC: COSV64732350;