rs1057519904

Positions:

• chr6-27872233-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_003533.3(H3C11):​c.83A>T​(p.Lys28Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in UniProt as Likely_pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: H3C11 NM_003533.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.81

Genes affected

H3C11 (HGNC:4771): (H3 clustered histone 11) 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 H3 family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the small histone gene cluster on chromosome 6p22-p21.3. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a modified_residue N6-lactoyllysine; alternate (size 0) in uniprot entity H31_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-27872233-T-A is Pathogenic according to our data. Variant chr6-27872233-T-A is described in UniProt as null. Variant chr6-27872233-T-A is described in UniProt as null. Variant chr6-27872233-T-A is described in UniProt as null. Variant chr6-27872233-T-A is described in UniProt as null. Variant chr6-27872233-T-A is described in UniProt as null. Variant chr6-27872233-T-A is described in UniProt as null. Variant chr6-27872233-T-A is described in UniProt as null. Variant chr6-27872233-T-A is described in UniProt as null. Variant chr6-27872233-T-A is described in UniProt as null. Variant chr6-27872233-T-A is described in UniProt as null. Variant chr6-27872233-T-A is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
H3C11	NM_003533.3	c.83A>T	p.Lys28Met	missense_variant	1/1	ENST00000616365.2	NP_003524.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
H3C11	ENST00000616365.2	c.83A>T	p.Lys28Met	missense_variant	1/1	6	NM_003533.3	ENSP00000483283.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Brainstem glioma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the head and neck Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Benign	0.88
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.73	T
PrimateAI	Pathogenic	0.81	D
Sift4G	Uncertain	0.015	D
Vest4		0.62
MVP		0.64
ClinPred		0.97	D
GERP RS		4.1
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519904; hg19: chr6-27840011;