chr6-27831472-T-C

Variant names:

• chr6-27831472-T-C
• rs1269093248
• NM_003541.3:c.56A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003541.3(H4C12):​c.56A>G​(p.His19Arg) 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H19H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: H4C12 NM_003541.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.24
• Publications: 0 publications found

Genes affected

H4C12 (HGNC:4784): (H4 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 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39275953).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003541.3. 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
	H4C12	NM_003541.3	MANE Select	c.56A>G	p.His19Arg	missense	Exon 1 of 1	NP_003532.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H4C12	ENST00000611927.2	TSL:6 MANE Select	c.56A>G	p.His19Arg	missense	Exon 1 of 1	ENSP00000479794.2	P62805
	H4C12	ENST00000718434.1		c.56A>G	p.His19Arg	missense	Exon 1 of 1	ENSP00000520819.1	P62805

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000292 AC: 4 AN: 1368660 Hom.: 0 Cov.: 34 AF XY: 0.00000298 AC XY: 2 AN XY: 670876

African (AFR) AF: 0.0000331 AC: 1 AN: 30216

American (AMR) AF: 0.00 AC: 0 AN: 29344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19932

East Asian (EAS) AF: 0.00 AC: 0 AN: 38900

South Asian (SAS) AF: 0.00 AC: 0 AN: 70790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5296

European-Non Finnish (NFE) AF: 0.00000281 AC: 3 AN: 1068006

Other (OTH) AF: 0.00 AC: 0 AN: 56234

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	20
DANN	Benign	0.91
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.49	T
PhyloP100		7.2
PrimateAI	Pathogenic	0.87	D
Sift4G	Uncertain	0.050	T
Vest4		0.54
MVP		0.061
ClinPred		0.98	D
GERP RS		4.0
PromoterAI		0.082	Neutral
gMVP		0.017
Mutation Taster		=36/64	disease causing

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: rs1269093248; hg19: chr6-27799250;