Variant 1-226065693-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5

The NM_002107.7(H3-3A):c.166C>A(p.Gln56Lys) 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 Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

H3-3A
NM_002107.7 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.91

Variant links:

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 links:

H3-3A (HGNC:):

H3-3A links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a chain Histone H3.3 (size 134) in uniprot entity H33_HUMAN there are 33 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 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.862

PP5

Variant 1-226065693-C-A is Pathogenic according to our data. Variant chr1-226065693-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1183978.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
H3-3A	NM_002107.7 linkuse as main transcript	c.166C>A	p.Gln56Lys	missense_variant	3/4	ENST00000366815.10	NP_002098.1	P84243B2R4P9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
H3-3A	ENST00000366815.10 linkuse as main transcript	c.166C>A	p.Gln56Lys	missense_variant	3/4	1	NM_002107.7	ENSP00000355780.3		P84243

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Short stature;C0454644:Delayed speech and language development;C0557874:Global developmental delay;C2711610:Brain imaging abnormality;C3714756:Intellectual disability

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Baylor Genetics

Jul 15, 2021

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

T;T;T;T

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

.;.;D;.

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.86

D;D;D;D

MetaSVM

Benign

-0.37

MutationAssessor

Pathogenic

3.6

H;H;.;H

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

.;.;D;.

Sift4G

Uncertain

0.029

D;D;D;D

Polyphen

0.97

D;D;D;D

Vest4

0.84

MutPred

0.51

Gain of methylation at Q56 (P = 0.0673);Gain of methylation at Q56 (P = 0.0673);Gain of methylation at Q56 (P = 0.0673);Gain of methylation at Q56 (P = 0.0673);

MVP

0.94

MPC

2.4

ClinPred

1.0

GERP RS

5.0

Varity_R

0.98

gMVP

1.0

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.

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