NM_003510.3:c.5C>G

Variant names:

• chr6-27838335-G-C
• rs188027160
• NM_003510.3:c.5C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_003510.3(H2AC15):​c.5C>G​(p.Ser2Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,423,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. S2L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: H2AC15 NM_003510.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.12
• Publications: 2 publications found

Genes affected

H2AC15 (HGNC:4726): (H2A clustered histone 15) 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]

H2BC15 (HGNC:4749): (H2B clustered histone 15) 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 H2B 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

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a modified_residue N-acetylserine (size 0) in uniprot entity H2A1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H2AC15	NM_003510.3	c.5C>G	p.Ser2Trp	missense_variant	Exon 1 of 1	ENST00000618958.2	NP_003501.1
H2BC15	NM_003520.4	c.-327G>C		upstream_gene_variant		ENST00000612898.2	NP_003511.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H2AC15	ENST00000618958.2	c.5C>G	p.Ser2Trp	missense_variant	Exon 1 of 1	6	NM_003510.3	ENSP00000482431.2
H2AC15	ENST00000718365.1	c.5C>G	p.Ser2Trp	missense_variant	Exon 1 of 1			ENSP00000520791.1
H2BC15	ENST00000612898.2	c.-327G>C		upstream_gene_variant		6	NM_003520.4	ENSP00000483903.1
H2BC15	ENST00000449538.3	n.-327G>C		upstream_gene_variant		1		ENSP00000446031.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000455 AC: 1 AN: 220010 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000985

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1423522 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 704750

African (AFR) AF: 0.00 AC: 0 AN: 32182

American (AMR) AF: 0.00 AC: 0 AN: 38552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23348

East Asian (EAS) AF: 0.00 AC: 0 AN: 39322

South Asian (SAS) AF: 0.00 AC: 0 AN: 81250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5540

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1092734

Other (OTH) AF: 0.00 AC: 0 AN: 58604

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	21
DANN	Benign	0.92
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Pathogenic	0.90	D
PhyloP100		4.1
PrimateAI	Pathogenic	0.84	D
Sift4G	Pathogenic	0.0	D
Vest4		0.66
MVP		0.30
ClinPred		0.99	D
GERP RS		4.5
PromoterAI		-0.037	Neutral
gMVP		0.24
Mutation Taster		=84/16	polymorphism

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: rs188027160; hg19: chr6-27806113;