6-26246922-T-A

Variant names:

• chr6-26246922-T-A
• NM_003547.3:c.56A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003547.3(H4C7):​c.56A>T​(p.His19Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: H4C7 NM_003547.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.60

Genes affected

H4C7 (HGNC:4792): (H4 clustered histone 7) 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 large histone gene cluster on chromosome 6. [provided by RefSeq, Aug 2015]

ENSG00000291336 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H4C7	NM_003547.3	c.56A>T	p.His19Leu	missense_variant	Exon 1 of 1	ENST00000611444.2	NP_003538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H4C7	ENST00000611444.2	c.56A>T	p.His19Leu	missense_variant	Exon 1 of 1	6	NM_003547.3	ENSP00000477870.2
ENSG00000291336	ENST00000707189.1	n.999+122751T>A		intron_variant	Intron 1 of 1
ENSG00000291338	ENST00000707191.1	n.1000+88801T>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.56A>T (p.H19L) alteration is located in exon 1 (coding exon 1) of the HIST1H4G gene. This alteration results from a A to T substitution at nucleotide position 56, causing the histidine (H) at amino acid position 19 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.60	T
PrimateAI	Pathogenic	0.83	D
Sift4G	Uncertain	0.024	D
Polyphen		0.99	D
Vest4		0.81
MutPred		0.56		Gain of helix (P = 0.005);
MVP		0.40
ClinPred		0.98	D
GERP RS		3.3
Varity_R		0.098
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-26247150;