6-26027213-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_003544.3(H4C2):​c.40G>C​(p.Gly14Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,970 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

H4C2
NM_003544.3 missense

Scores

4
2
8

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.66
Variant links:
Genes affected
H4C2 (HGNC:4789): (H4 clustered histone 2) 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 5 ACMG points.

PM1
In a chain Histone H4 (size 101) in uniprot entity H4_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_003544.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.773

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
H4C2NM_003544.3 linkc.40G>C p.Gly14Arg missense_variant Exon 1 of 1 ENST00000377745.5 NP_003535.1 P62805B2R4R0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
H4C2ENST00000377745.5 linkc.40G>C p.Gly14Arg missense_variant Exon 1 of 1 6 NM_003544.3 ENSP00000366974.2 P62805

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459970
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
725842
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.030
CADD
Benign
22
DANN
Benign
0.94
Eigen
Benign
0.14
Eigen_PC
Benign
0.094
FATHMM_MKL
Uncertain
0.96
D
M_CAP
Benign
0.0088
T
MetaRNN
Pathogenic
0.77
D
MetaSVM
Benign
-0.44
T
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-6.5
D
Sift
Benign
0.10
T
Sift4G
Benign
0.13
T
Vest4
0.74
MVP
0.13
ClinPred
0.96
D
GERP RS
4.7
RBP_binding_hub_radar
1.0
RBP_regulation_power_radar
2.1
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.21
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.21
Position offset: 6

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: chr6-26027441; API