chr4-99949025-T-C

Variant names:

• chr4-99949025-T-C
• rs61203457
• NM_002106.4:c.196-85A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 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. Variant has been reported in ClinVar as (no stars).

• 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
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -7 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002106.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H2AZ1	NM_002106.4	MANE Select	c.196-85A>G		intron	N/A	NP_002097.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H2AZ1	ENST00000296417.6	TSL:1 MANE Select	c.196-85A>G		intron	N/A	ENSP00000296417.5
	H2AZ1	ENST00000511348.1	TSL:1	n.904A>G		non_coding_transcript_exon	Exon 2 of 2
	H2AZ1	ENST00000511319.5	TSL:1	n.721-85A>G		intron	N/A

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

African (AFR) AF: 0.404 AC: 7156 AN: 17726

American (AMR) AF: 0.221 AC: 7815 AN: 35284

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 6399 AN: 18464

East Asian (EAS) AF: 0.205 AC: 7398 AN: 36064

South Asian (SAS) AF: 0.155 AC: 9941 AN: 64012

European-Finnish (FIN) AF: 0.248 AC: 12840 AN: 51670

Middle Eastern (MID) AF: 0.268 AC: 1105 AN: 4128

European-Non Finnish (NFE) AF: 0.225 AC: 95638 AN: 424740

Other (OTH) AF: 0.244 AC: 8393 AN: 34400

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

African (AFR) AF: 0.391 AC: 16216 AN: 41434

American (AMR) AF: 0.229 AC: 3503 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1204 AN: 3470

East Asian (EAS) AF: 0.148 AC: 766 AN: 5176

South Asian (SAS) AF: 0.156 AC: 751 AN: 4812

European-Finnish (FIN) AF: 0.243 AC: 2563 AN: 10552

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15870 AN: 67976

Other (OTH) AF: 0.285 AC: 601 AN: 2110

Alfa AF: 0.251 Hom.: 2038

Bravo AF: 0.281

Asia WGS AF: 0.175 AC: 610 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.0
DANN	Benign	0.57
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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