Genetic Variant NM_002107.7:c.121C>T (chr1-226064472-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Bryant-Li-Bhoj neurodevelopmental syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Illumina

H3-3A links:

ENSG00000299101 (HGNC:):

ENSG00000299101 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a region_of_interest Disordered (size 42) in uniprot entity H33_HUMAN there are 6 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 the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.1568 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 1183977.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002107.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
H3-3A	NM_002107.7	MANE Select	c.121C>T	p.Arg41Cys	missense	Exon 2 of 4	NP_002098.1	P84243
H3-3A	NM_001379043.1		c.121C>T	p.Arg41Cys	missense	Exon 3 of 5	NP_001365972.1	P84243
H3-3A	NM_001379045.1		c.121C>T	p.Arg41Cys	missense	Exon 3 of 5	NP_001365974.1	P84243

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
H3-3A	ENST00000366815.10	TSL:1 MANE Select	c.121C>T	p.Arg41Cys	missense	Exon 2 of 4	ENSP00000355780.3	P84243
H3-3A	ENST00000366813.1	TSL:1	c.121C>T	p.Arg41Cys	missense	Exon 1 of 3	ENSP00000355778.1	P84243
H3-3A	ENST00000921925.1		c.121C>T	p.Arg41Cys	missense	Exon 2 of 4	ENSP00000591984.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bryant-Li-Bhoj neurodevelopmental syndrome 1 (1)

Short stature;C0454644:Delayed speech and language development;C0557874:Global developmental delay;C2711610:Brain imaging abnormality;C3714756:Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.63

MetaSVM

Benign

-0.35

MutationAssessor

Pathogenic

3.3

PhyloP100

6.0

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.3

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.032

Polyphen

0.011

Vest4

0.79

MutPred

0.41

Loss of solvent accessibility (P = 0.0079)

MVP

0.88

MPC

2.4

ClinPred

1.0

GERP RS

4.3

PromoterAI

0.0094

Neutral

(source)

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

Varity_R

0.96

gMVP

0.96

Mutation Taster

=49/51

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over