chr6-26285397-T-G
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_003543.4(H4C8):āc.103A>Cā(p.Ile35Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,614,260 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000059 ( 1 hom., cov: 33)
Exomes š: 0.0000034 ( 0 hom. )
Consequence
H4C8
NM_003543.4 missense
NM_003543.4 missense
Scores
1
3
8
Clinical Significance
Conservation
PhyloP100: 6.21
Genes affected
H4C8 (HGNC:4788): (H4 clustered histone 8) 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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
In a helix (size 9) in uniprot entity H4_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_003543.4
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
H4C8 | NM_003543.4 | c.103A>C | p.Ile35Leu | missense_variant | 1/1 | ENST00000377727.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
H4C8 | ENST00000377727.2 | c.103A>C | p.Ile35Leu | missense_variant | 1/1 | NM_003543.4 | P1 | ||
ENST00000687171.2 | n.46T>G | non_coding_transcript_exon_variant | 1/1 | ||||||
ENST00000707189.1 | n.999+161226T>G | intron_variant, non_coding_transcript_variant | |||||||
ENST00000707191.1 | n.1000+127276T>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152248Hom.: 1 Cov.: 33
GnomAD3 genomes
AF:
AC:
9
AN:
152248
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251320Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135818
GnomAD3 exomes
AF:
AC:
1
AN:
251320
Hom.:
AF XY:
AC XY:
1
AN XY:
135818
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461894Hom.: 0 Cov.: 73 AF XY: 0.00000413 AC XY: 3AN XY: 727248
GnomAD4 exome
AF:
AC:
5
AN:
1461894
Hom.:
Cov.:
73
AF XY:
AC XY:
3
AN XY:
727248
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152366Hom.: 1 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74520
GnomAD4 genome
AF:
AC:
9
AN:
152366
Hom.:
Cov.:
33
AF XY:
AC XY:
8
AN XY:
74520
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ExAC
AF:
AC:
1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 03, 2023 | The c.103A>C (p.I35L) alteration is located in exon 1 (coding exon 1) of the HIST1H4H gene. This alteration results from a A to C substitution at nucleotide position 103, causing the isoleucine (I) at amino acid position 35 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
Sift4G
Benign
T;T
Vest4
MVP
0.19
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at