Variant 1-226064472-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP5

The NM_002107.7(H3-3A):c.121C>T(p.Arg41Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 31)

Consequence

H3-3A
NM_002107.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 6.00

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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, 7 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.

PP5

Variant 1-226064472-C-T is Pathogenic according to our data. Variant chr1-226064472-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1183977.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
H3-3A	NM_002107.7 linkuse as main transcript	c.121C>T	p.Arg41Cys	missense_variant	2/4	ENST00000366815.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
H3-3A	ENST00000366815.10 linkuse as main transcript	c.121C>T	p.Arg41Cys	missense_variant	2/4	1	NM_002107.7	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

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

- -

Bryant-Li-Bhoj neurodevelopmental syndrome 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Benign

0.95

DEOGEN2

Benign

0.29

T;T;T;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

.;.;D;.

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.63

D;D;D;D

MetaSVM

Benign

-0.35

MutationAssessor

Pathogenic

3.3

M;M;.;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.3

D;D;D;D

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

.;.;D;.

Sift4G

Uncertain

0.032

D;D;D;D

Polyphen

0.011

B;B;D;B

Vest4

0.79

MutPred

0.41

Loss of solvent accessibility (P = 0.0079);Loss of solvent accessibility (P = 0.0079);Loss of solvent accessibility (P = 0.0079);Loss of solvent accessibility (P = 0.0079);

MVP

0.88

MPC

2.4

ClinPred

1.0

GERP RS

4.3

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

Varity_R

0.96

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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