17-75779151-AG-CA

Variant names:

• chr17-75779151-AG-CA
• NM_005324.5:c.23_24delCTinsTG
• H3-3B p.Ala8Val

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS1_Moderate PM1 PP2 PP3

The NM_005324.5(H3-3B):​c.23_24delCTinsTG​(p.Ala8Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: H3-3B NM_005324.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.49
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Bryant-Li-Bhoj neurodevelopmental syndrome 2

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

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

• PS1: Transcript NM_005324.5 (H3-3B) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_005324.5
• PP2: Missense variant in the H3-3B gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.8781 (below the threshold of 3.09). Trascript score misZ: 4.0007 (above the threshold of 3.09). GenCC associations: The gene is linked to Bryant-Li-Bhoj neurodevelopmental syndrome 2.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005324.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H3-3B	NM_005324.5	MANE Select	c.23_24delCTinsTG	p.Ala8Val	missense	N/A	NP_005315.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H3-3B	ENST00000254810.8	TSL:1 MANE Select	c.23_24delCTinsTG	p.Ala8Val	missense	N/A	ENSP00000254810.3	P84243
	H3-3B	ENST00000587171.1	TSL:2	c.23_24delCTinsTG	p.Ala8Val	missense	N/A	ENSP00000468484.1	K7ES00
	H3-3B	ENST00000852232.1		c.23_24delCTinsTG	p.Ala8Val	missense	N/A	ENSP00000522291.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-73775232;