NM_002106.4:c.161A>G

Variant summary

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

The NM_002106.4(H2AZ1):​c.161A>G​(p.Tyr54Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

H2AZ1
NM_002106.4 missense

Scores

14
4
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.20
Variant links:
Genes affected
H2AZ1 (HGNC:4741): (H2A.Z variant histone 1) 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 encodes a replication-independent member of the histone H2A family that is distinct from other members of the family. Studies in mice have shown that this particular histone is required for embryonic development and indicate that lack of functional histone H2A leads to embryonic lethality. [provided by RefSeq, Jul 2008]

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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, 0.924

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
H2AZ1NM_002106.4 linkc.161A>G p.Tyr54Cys missense_variant Exon 3 of 5 ENST00000296417.6 NP_002097.1 P0C0S5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
H2AZ1ENST00000296417.6 linkc.161A>G p.Tyr54Cys missense_variant Exon 3 of 5 1 NM_002106.4 ENSP00000296417.5 P0C0S5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 04, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.161A>G (p.Y54C) alteration is located in exon 3 (coding exon 3) of the H2AFZ gene. This alteration results from a A to G substitution at nucleotide position 161, causing the tyrosine (Y) at amino acid position 54 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
0.96
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.55
D
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.89
D
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.92
D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Pathogenic
4.0
H
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-7.9
D
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.91
MutPred
0.73
Loss of glycosylation at T50 (P = 0.029);
MVP
0.92
MPC
4.0
ClinPred
1.0
D
GERP RS
3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
1.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-100870464; API