6-26199137-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021065.3(H2AC7):​c.107G>A​(p.Arg36His) variant causes a missense change. The variant allele was found at a frequency of 0.000105 in 1,614,070 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

H2AC7
NM_021065.3 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.02
Variant links:
Genes affected
H2AC7 (HGNC:4729): (H2A clustered histone 7) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. This structure consists of approximately 146 bp of DNA wrapped around a nucleosome, an 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 H2A family. Transcripts from this gene lack polyA tails; instead, they contain a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6p22-p21.3. [provided by RefSeq, Aug 2015]
H3C4 (HGNC:4767): (H3 clustered histone 4) 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 H3 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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
H2AC7NM_021065.3 linkc.107G>A p.Arg36His missense_variant Exon 1 of 1 ENST00000341023.2 NP_066409.1 P20671B2R5B6
H3C4NM_003530.4 linkc.-298G>A 5_prime_UTR_variant Exon 1 of 2 NP_003521.2 P68431

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
H2AC7ENST00000341023.2 linkc.107G>A p.Arg36His missense_variant Exon 1 of 1 6 NM_021065.3 ENSP00000341094.2 P20671
ENSG00000282988ENST00000635200.1 linkc.107G>A p.Arg36His missense_variant Exon 1 of 2 3 ENSP00000489311.1 A0A0U1RR32

Frequencies

GnomAD3 genomes
AF:
0.0000788
AC:
12
AN:
152232
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.000162
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000997
AC:
25
AN:
250698
Hom.:
0
AF XY:
0.0000958
AC XY:
13
AN XY:
135770
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.000212
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000107
AC:
157
AN:
1461838
Hom.:
1
Cov.:
32
AF XY:
0.000106
AC XY:
77
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000125
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152232
Hom.:
0
Cov.:
33
AF XY:
0.000108
AC XY:
8
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.000162
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000115
Hom.:
0
Bravo
AF:
0.0000945
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000107
AC:
13
EpiCase
AF:
0.000436
EpiControl
AF:
0.000296

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Apr 30, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.107G>A (p.R36H) alteration is located in exon 1 (coding exon 1) of the HIST1H2AD gene. This alteration results from a G to A substitution at nucleotide position 107, causing the arginine (R) at amino acid position 36 to be replaced by a histidine (H). 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
0.92
BayesDel_addAF
Benign
-0.030
T
BayesDel_noAF
Uncertain
0.0
CADD
Uncertain
24
DANN
Benign
0.84
DEOGEN2
Benign
0.25
.;.;T
Eigen
Benign
-0.14
Eigen_PC
Benign
-0.19
FATHMM_MKL
Benign
0.68
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Benign
0.026
D
MetaRNN
Uncertain
0.58
D;D;D
MetaSVM
Benign
-0.86
T
MutationAssessor
Uncertain
2.5
.;.;M
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-3.9
.;.;D
REVEL
Benign
0.27
Sift
Uncertain
0.0080
.;.;D
Sift4G
Uncertain
0.045
.;D;T
Polyphen
0.17
.;.;B
Vest4
0.50, 0.56
MVP
0.75
MPC
0.15
ClinPred
0.47
T
GERP RS
3.7
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.7
Varity_R
0.61
gMVP
0.21

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

LitVar

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

Other links and lift over

dbSNP: rs368444246; hg19: chr6-26199365; API