6-27892786-C-T

Position:

• chr6-27892786-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_003514.2(H2AC17):​c.364G>A​(p.Glu122Lys) 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 benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: H2AC17 NM_003514.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.37

Genes affected

H2AC17 (HGNC:4735): (H2A clustered histone 17) 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 H2A 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]

H3C12 (HGNC:4774): (H3 clustered histone 12) 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-27892786-C-T is Pathogenic according to our data. Variant chr6-27892786-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 800317.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3512636). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
H2AC17	NM_003514.2	c.364G>A	p.Glu122Lys	missense_variant	1/1	ENST00000359611.4	NP_003505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
H2AC17	ENST00000359611.4	c.364G>A	p.Glu122Lys	missense_variant	1/1	6	NM_003514.2	ENSP00000352627.3
H3C12	ENST00000479986.1	n.321G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Multiple myeloma Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center

Aug 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Benign	0.93
Eigen	Benign	0.021
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.18
Sift	Uncertain	0.021	D
Sift4G	Benign	0.56	T
Vest4		0.55
MutPred		0.41		Gain of MoRF binding (P = 0.0015);
MVP		0.30
MPC		0.57
ClinPred		0.98	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
gMVP		0.29

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: rs1581495906; hg19: chr6-27860564; COSMIC: COSV58153478; COSMIC: COSV58153478;