4-99949218-T-G

Position:

• chr4-99949218-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002106.4(H2AZ1):​c.195+55A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,069,368 control chromosomes in the GnomAD database, including 28,644 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (4765 hom., cov: 31)
  • Exomes 𝑓: 0.22 (23879 hom.)
• Consequence: H2AZ1 NM_002106.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.206

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
H2AZ1	NM_002106.4	c.195+55A>C		intron_variant		ENST00000296417.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
H2AZ1	ENST00000296417.6	c.195+55A>C		intron_variant		1	NM_002106.4	P4

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37419 AN: 151698 Hom.: 4762 Cov.: 31

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.260

GnomAD4 exome AF: 0.223 AC: 204625 AN: 917552 Hom.: 23879 Cov.: 12 AF XY: 0.221 AC XY: 104611 AN XY: 472310

Gnomad4 AFR exome AF: 0.302

Gnomad4 AMR exome AF: 0.214

Gnomad4 ASJ exome AF: 0.345

Gnomad4 EAS exome AF: 0.204

Gnomad4 SAS exome AF: 0.155

Gnomad4 FIN exome AF: 0.248

Gnomad4 NFE exome AF: 0.223

Gnomad4 OTH exome AF: 0.232

GnomAD4 genome AF: 0.247 AC: 37439 AN: 151816 Hom.: 4765 Cov.: 31 AF XY: 0.242 AC XY: 17926 AN XY: 74194

Gnomad4 AFR AF: 0.294

Gnomad4 AMR AF: 0.219

Gnomad4 ASJ AF: 0.347

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.242

Gnomad4 NFE AF: 0.233

Gnomad4 OTH AF: 0.260

Alfa AF: 0.192 Hom.: 726

Bravo AF: 0.248

Asia WGS AF: 0.168 AC: 586 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	13
DANN	Benign	0.54

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

Other links and lift over

dbSNP: rs2276939; hg19: chr4-100870375; COSMIC: COSV56454776; COSMIC: COSV56454776;