rs2113784282

Variant names:

• chr6-26104045-C-G
• rs2113784282
• NM_003542.4:c.98C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-26104045-C-G
• chr6-26104045-C-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_003542.4(H4C3):​c.98C>G​(p.Pro33Arg) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P33L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: H4C3 NM_003542.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.85
• Publications: 0 publications found

Genes affected

H4C3 (HGNC:4787): (H4 clustered histone 3) 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 is intronless and encodes a replication-dependent histone that is a member of the histone H4 family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6. [provided by RefSeq, Aug 2015]

H2BC4 (HGNC:4757): (H2B clustered histone 4) 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. The protein has antibacterial and antifungal antimicrobial activity. The main transcript variant of this gene is intronless and encodes a replication-dependent histone that is a member of the histone H2B family. This transcript variant lacks a polyA tail but instead contains a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6. [provided by RefSeq, Apr 2020]

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-26104045-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2443367.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.016488 (below the threshold of 3.09). Trascript score misZ: -0.94881 (below the threshold of 3.09). GenCC associations: The gene is linked to Tessadori-van Haaften neurodevelopmental syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851
• PP5: Variant 6-26104045-C-G is Pathogenic according to our data. Variant chr6-26104045-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2443610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003542.4. 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
	H4C3	NM_003542.4	MANE Select	c.98C>G	p.Pro33Arg	missense	Exon 1 of 1	NP_003533.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H4C3	ENST00000377803.4	TSL:6 MANE Select	c.98C>G	p.Pro33Arg	missense	Exon 1 of 1	ENSP00000367034.3	P62805
	H2BC4	ENST00000957524.1		c.*10-13011G>C		intron	N/A	ENSP00000627583.1
	H2BC4	ENST00000707188.1		n.*10-13011G>C		intron	N/A	ENSP00000516775.1	P62807

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Tessadori-van Haaften neurodevelopmental syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	-0.20	T
PhyloP100		7.8
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-8.7	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Vest4		0.94
MutPred		0.43		Gain of disorder (P = 0.1038)
MVP		0.43
ClinPred		1.0	D
GERP RS		4.6
PromoterAI		-0.073	Neutral
gMVP		0.072
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs2113784282; hg19: chr6-26104273;