Variant 17-75779077-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP5_Moderate

The NM_005324.5(H3-3B):c.98C>T(p.Thr33Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

H3-3B
NM_005324.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.49

Variant links:

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]

H3-3B links:

H3-3B (HGNC:):

H3-3B links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a region_of_interest Disordered (size 42) in uniprot entity H33_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_005324.5

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-75779077-G-A is Pathogenic according to our data. Variant chr17-75779077-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2571003.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
H3-3B	NM_005324.5 linkuse as main transcript	c.98C>T	p.Thr33Ile	missense_variant	2/4	ENST00000254810.8	NP_005315.1	P84243B2R4P9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
H3-3B	ENST00000254810.8 linkuse as main transcript	c.98C>T	p.Thr33Ile	missense_variant	2/4	1	NM_005324.5	ENSP00000254810.3		P84243

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454452

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723798

show subpopulations

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

H3-3B: PS2, PM2, PP2, PP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.0035

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.063

.;T;.;.;.;.;T;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.71

.;T;T;.;.;T;T;T

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.62

D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.39

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.4

D;.;.;.;.;.;.;.

REVEL

Uncertain

0.31

Sift4G

Uncertain

0.044

D;T;T;D;D;D;D;.

Vest4

0.64

MutPred

0.33

Loss of phosphorylation at T33 (P = 0.0098);Loss of phosphorylation at T33 (P = 0.0098);Loss of phosphorylation at T33 (P = 0.0098);Loss of phosphorylation at T33 (P = 0.0098);Loss of phosphorylation at T33 (P = 0.0098);Loss of phosphorylation at T33 (P = 0.0098);Loss of phosphorylation at T33 (P = 0.0098);Loss of phosphorylation at T33 (P = 0.0098);

MVP

0.94

MPC

1.9

ClinPred

1.0

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.82

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over