chr6-26199096-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003530.4(H3C4):​c.-257G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000809 in 1,614,178 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00083 ( 4 hom. )

Consequence

H3C4
NM_003530.4 5_prime_UTR_premature_start_codon_gain

Scores

4
7
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.75
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.10050723).
BS2
High Homozygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
H2AC7NM_021065.3 linkc.148G>T p.Val50Leu missense_variant Exon 1 of 1 ENST00000341023.2 NP_066409.1 P20671B2R5B6
H3C4NM_003530.4 linkc.-257G>T 5_prime_UTR_premature_start_codon_gain_variant Exon 1 of 2 NP_003521.2 P68431
H3C4NM_003530.4 linkc.-257G>T 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.148G>T p.Val50Leu missense_variant Exon 1 of 1 6 NM_021065.3 ENSP00000341094.2 P20671
ENSG00000282988ENST00000635200.1 linkc.148G>T p.Val50Leu missense_variant Exon 1 of 2 3 ENSP00000489311.1 A0A0U1RR32

Frequencies

GnomAD3 genomes
AF:
0.000591
AC:
90
AN:
152238
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000289
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00186
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000999
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000570
AC:
143
AN:
250668
Hom.:
1
AF XY:
0.000656
AC XY:
89
AN XY:
135720
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000202
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00140
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000776
Gnomad OTH exome
AF:
0.000654
GnomAD4 exome
AF:
0.000833
AC:
1217
AN:
1461822
Hom.:
4
Cov.:
32
AF XY:
0.000861
AC XY:
626
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00144
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.000935
Gnomad4 OTH exome
AF:
0.000580
GnomAD4 genome
AF:
0.000584
AC:
89
AN:
152356
Hom.:
0
Cov.:
33
AF XY:
0.000617
AC XY:
46
AN XY:
74502
show subpopulations
Gnomad4 AFR
AF:
0.000289
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00165
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00100
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000605
Hom.:
0
Bravo
AF:
0.000476
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000814
AC:
7
ExAC
AF:
0.000494
AC:
60
EpiCase
AF:
0.00104
EpiControl
AF:
0.000889

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
May 11, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.148G>T (p.V50L) alteration is located in exon 1 (coding exon 1) of the HIST1H2AD gene. This alteration results from a G to T substitution at nucleotide position 148, causing the valine (V) at amino acid position 50 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
Pathogenic
0.99
BayesDel_addAF
Benign
-0.056
T
BayesDel_noAF
Uncertain
0.11
CADD
Benign
22
DANN
Benign
0.96
DEOGEN2
Benign
0.32
.;.;T
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.10
T;T;T
MetaSVM
Benign
-0.33
T
MutationAssessor
Pathogenic
3.7
.;.;H
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-2.5
.;.;D
REVEL
Benign
0.28
Sift
Uncertain
0.0060
.;.;D
Sift4G
Pathogenic
0.0010
.;D;D
Polyphen
0.15
.;.;B
Vest4
0.84, 0.89
MutPred
0.69
Loss of phosphorylation at Y51 (P = 0.1494);Loss of phosphorylation at Y51 (P = 0.1494);Loss of phosphorylation at Y51 (P = 0.1494);
MVP
0.56
MPC
0.13
ClinPred
0.24
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.55
gMVP
0.43

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs142347437; hg19: chr6-26199324; API