dbSNP rs752225254: H2AC7:p.Gly3Val (chr6-26199236-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_021065.3(H2AC7):c.8G>T(p.Gly3Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,443,436 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G3A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

H2AC7
NM_021065.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H2AC7	NM_021065.3 link	c.8G>T	p.Gly3Val	missense_variant	Exon 1 of 1	ENST00000341023.2	NP_066409.1	P20671B2R5B6
H3C4	NM_003530.4 link	c.-397G>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.8G>T	p.Gly3Val	missense_variant	Exon 1 of 1	6	NM_021065.3	ENSP00000341094.2		P20671
ENSG00000282988	ENST00000635200.1 link	c.8G>T	p.Gly3Val	missense_variant	Exon 1 of 2	3		ENSP00000489311.1		A0A0U1RR32

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000433

AC:

AN:

230788

Hom.:

AF XY:

0.00000796

AC XY:

AN XY:

125614

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:

0.00000924

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000346

AC:

AN:

1443436

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718002

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000451

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.45

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.30

.;.;T

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

.;.;H

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.7

.;.;D

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

.;.;D

Sift4G

Uncertain

0.017

.;D;D

Polyphen

1.0

.;.;D

Vest4

0.64, 0.56

MutPred

0.40

Gain of sheet (P = 0.0166);Gain of sheet (P = 0.0166);Gain of sheet (P = 0.0166);

MVP

0.98

MPC

0.12

ClinPred

1.0

GERP RS

4.8

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.77

gMVP

0.11

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over