17-75779087-C-A

Variant names:

• chr17-75779087-C-A
• rs2143631293
• NM_005324.5:c.88G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_005324.5(H3-3B):​c.88G>T​(p.Ala30Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,454,422 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A30P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: H3-3B NM_005324.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.79
• 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 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_005324.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-75779087-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1339273.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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.

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.88G>T	p.Ala30Ser	missense	Exon 2 of 4	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.88G>T	p.Ala30Ser	missense	Exon 2 of 4	ENSP00000254810.3	P84243
	H3-3B	ENST00000587171.1	TSL:2	c.88G>T	p.Ala30Ser	missense	Exon 2 of 3	ENSP00000468484.1	K7ES00
	H3-3B	ENST00000852232.1		c.88G>T	p.Ala30Ser	missense	Exon 2 of 4	ENSP00000522291.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454422 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723852

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32880

American (AMR) AF: 0.00 AC: 0 AN: 42418

Ashkenazi Jewish (ASJ) AF: 0.0000389 AC: 1 AN: 25724

East Asian (EAS) AF: 0.00 AC: 0 AN: 39474

South Asian (SAS) AF: 0.00 AC: 0 AN: 85830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109246

Other (OTH) AF: 0.00 AC: 0 AN: 60000

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.047	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.74	T
PhyloP100		5.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.20
Sift4G	Benign	0.13	T
Vest4		0.50
MutPred		0.37		Gain of phosphorylation at A30 (P = 0.0041)
MVP		0.98
MPC		1.7
ClinPred		0.99	D
GERP RS		5.1
PromoterAI		-0.073	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.75

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

Other links and lift over

dbSNP: rs2143631293; hg19: chr17-73775168;