6-27873498-C-G

Variant names:

• chr6-27873498-C-G
• rs751027005
• NM_003546.3:c.13G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003546.3(H4C13):​c.13G>C​(p.Gly5Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,124 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. G5S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: H4C13 NM_003546.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.55
• Publications: 0 publications found

Genes affected

H4C13 (HGNC:4791): (H4 clustered histone 13) 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 small histone gene cluster on chromosome 6p22-p21.3. [provided by RefSeq, Aug 2015]

ENSG00000305770 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003546.3. 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
	H4C13	NM_003546.3	MANE Select	c.13G>C	p.Gly5Arg	missense	Exon 1 of 1	NP_003537.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H4C13	ENST00000618305.2	TSL:6 MANE Select	c.13G>C	p.Gly5Arg	missense	Exon 1 of 1	ENSP00000480960.2	P62805
	ENSG00000305770	ENST00000812856.1		n.-132C>G		upstream_gene	N/A
	ENSG00000305770	ENST00000812857.1		n.-87C>G		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458124 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725128

African (AFR) AF: 0.00 AC: 0 AN: 33266

American (AMR) AF: 0.00 AC: 0 AN: 44238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25922

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 86034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109808

Other (OTH) AF: 0.00 AC: 0 AN: 60214

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.091
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.41	T
PhyloP100		7.5
PrimateAI	Pathogenic	0.90	D
Sift4G	Uncertain	0.049	D
Vest4		0.69
MVP		0.18
ClinPred		1.0	D
GERP RS		3.9
PromoterAI		0.032	Neutral
gMVP		0.87
Mutation Taster		=80/20	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: rs751027005; hg19: chr6-27841276;