17-75779174-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_005324.5(H3-3B):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000725 in 1,379,410 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: H3-3B NM_005324.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.62

Genes affected

H3-3B (HGNC:4765): (H3.3 histone B) 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 by this gene is a replication-independent histone that is a member of the histone H3 family. Pseudogenes of this gene have been identified on the X chromosome, and on chromosomes 5, 13 and 17. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
H3-3B	NM_005324.5	c.1A>G	p.Met1?	start_lost	2/4	ENST00000254810.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
H3-3B	ENST00000254810.8	c.1A>G	p.Met1?	start_lost	2/4	1	NM_005324.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1379410 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 682548

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.30e-7

Gnomad4 OTH exome AF: 0.00

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

GeneDx

Oct 11, 2021

Not observed in large population cohorts (Lek et al., 2016); Initiation codon variant in a gene for which loss-of-function is not a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Benign	22
Dann	Benign	0.95
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Uncertain	-2.4	N;.;.;.;.;.;.;.
REVEL	Uncertain	0.47
Sift4G	Uncertain	0.047	D;D;D;D;D;D;T;.
Vest4		0.94
MutPred		0.72		Loss of phosphorylation at T4 (P = 0.2623);Loss of phosphorylation at T4 (P = 0.2623);Loss of phosphorylation at T4 (P = 0.2623);Loss of phosphorylation at T4 (P = 0.2623);Loss of phosphorylation at T4 (P = 0.2623);Loss of phosphorylation at T4 (P = 0.2623);Loss of phosphorylation at T4 (P = 0.2623);Loss of phosphorylation at T4 (P = 0.2623);
MVP		0.99
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr17-73775255;