chr6-26199096-C-A

Variant names:

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

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]

H2AC7 links:

ENSG00000282988 (HGNC:):

ENSG00000282988 links:

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]

H3C4 links:

Genome browser will be placed here

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
H2AC7	NM_021065.3 link	c.148G>T	p.Val50Leu	missense_variant	Exon 1 of 1	ENST00000341023.2	NP_066409.1	P20671B2R5B6
H3C4	NM_003530.4 link	c.-257G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2		NP_003521.2	P68431
H3C4	NM_003530.4 link	c.-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
H2AC7	ENST00000341023.2 link	c.148G>T	p.Val50Leu	missense_variant	Exon 1 of 1	6	NM_021065.3	ENSP00000341094.2		P20671
ENSG00000282988	ENST00000635200.1 link	c.148G>T	p.Val50Leu	missense_variant	Exon 1 of 2	3		ENSP00000489311.1		A0A0U1RR32

Frequencies

GnomAD3 genomes

AF:

0.000591

AC:

AN:

152238

Hom.:

Cov.:

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.:

AF XY:

0.000656

AC XY:

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.:

Cov.:

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:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000617

AC XY:

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.:

Bravo

AF:

0.000476

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000494

AC:

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

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.32

.;.;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Pathogenic

3.7

.;.;H

PrimateAI

Pathogenic

0.87

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over