rs61203457

Positions:

• chr4-99949025-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_002106.4(H2AZ1):​c.196-85A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 838,506 control chromosomes in the GnomAD database, including 25,412 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 0.27 (6260 hom., cov: 32)
  • Exomes 𝑓: 0.23 (19152 hom.)
• Consequence: H2AZ1 NM_002106.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.162

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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
H2AZ1	NM_002106.4	c.196-85A>G		intron_variant		ENST00000296417.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
H2AZ1	ENST00000296417.6	c.196-85A>G		intron_variant		1	NM_002106.4	P4

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41764 AN: 151900 Hom.: 6255 Cov.: 32

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.286

GnomAD4 exome AF: 0.228 AC: 156685 AN: 686488 Hom.: 19152 Cov.: 9 AF XY: 0.226 AC XY: 82634 AN XY: 365850

Gnomad4 AFR exome AF: 0.404

Gnomad4 AMR exome AF: 0.221

Gnomad4 ASJ exome AF: 0.347

Gnomad4 EAS exome AF: 0.205

Gnomad4 SAS exome AF: 0.155

Gnomad4 FIN exome AF: 0.248

Gnomad4 NFE exome AF: 0.225

Gnomad4 OTH exome AF: 0.244

GnomAD4 genome AF: 0.275 AC: 41798 AN: 152018 Hom.: 6260 Cov.: 32 AF XY: 0.269 AC XY: 20005 AN XY: 74298

Gnomad4 AFR AF: 0.391

Gnomad4 AMR AF: 0.229

Gnomad4 ASJ AF: 0.347

Gnomad4 EAS AF: 0.148

Gnomad4 SAS AF: 0.156

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.233

Gnomad4 OTH AF: 0.285

Alfa AF: 0.249 Hom.: 1164

Bravo AF: 0.281

Asia WGS AF: 0.175 AC: 610 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.0
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.59		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61203457; hg19: chr4-100870182; COSMIC: COSV56454769; COSMIC: COSV56454769;