12-14771066-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_175054.2(H4C16):​c.19G>T​(p.Gly7Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000387 in 1,601,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G7D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

H4C16
NM_175054.2 missense

Scores

3
3
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.75
Variant links:
Genes affected
H4C16 (HGNC:20510): (H4 histone 16) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Nucleosomes consist of approximately 146 bp of DNA wrapped around a histone octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin 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; instead, they contain a palindromic termination element. [provided by RefSeq, Aug 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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_175054.2
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.21083218).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
H4C16NM_175054.2 linkc.19G>T p.Gly7Cys missense_variant Exon 1 of 1 ENST00000539745.2 NP_778224.1 P62805B2R4R0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
H4C16ENST00000539745.2 linkc.19G>T p.Gly7Cys missense_variant Exon 1 of 1 6 NM_175054.2 ENSP00000443017.1 P62805
H4C16ENST00000358064.3 linkn.19G>T non_coding_transcript_exon_variant Exon 1 of 2 1 ENSP00000350767.3 P62805

Frequencies

GnomAD3 genomes
AF:
0.000197
AC:
30
AN:
152206
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000489
AC:
12
AN:
245510
Hom.:
0
AF XY:
0.0000301
AC XY:
4
AN XY:
132924
show subpopulations
Gnomad AFR exome
AF:
0.000686
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000900
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000221
AC:
32
AN:
1449454
Hom.:
0
Cov.:
30
AF XY:
0.0000181
AC XY:
13
AN XY:
719366
show subpopulations
Gnomad4 AFR exome
AF:
0.000877
Gnomad4 AMR exome
AF:
0.0000230
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000335
GnomAD4 genome
AF:
0.000197
AC:
30
AN:
152324
Hom.:
0
Cov.:
33
AF XY:
0.000201
AC XY:
15
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.000722
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000230
Hom.:
0
Bravo
AF:
0.000227
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000659
AC:
8

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 14, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.19G>T (p.G7C) alteration is located in exon 1 (coding exon 1) of the HIST4H4 gene. This alteration results from a G to T substitution at nucleotide position 19, causing the glycine (G) at amino acid position 7 to be replaced by a cysteine (C). 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
Pathogenic
0.89
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.16
CADD
Uncertain
24
DANN
Uncertain
0.98
Eigen
Benign
0.017
Eigen_PC
Benign
-0.046
FATHMM_MKL
Uncertain
0.85
D
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.21
T
MetaSVM
Benign
-0.57
T
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-7.0
D
REVEL
Benign
0.18
Sift
Benign
0.033
D
Sift4G
Pathogenic
0.0010
D
Vest4
0.54
MVP
0.92
MPC
0.31
ClinPred
0.47
T
GERP RS
3.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs369222901; hg19: chr12-14924000; COSMIC: COSV63762391; COSMIC: COSV63762391; API