Genetic Variant H2AZ1:c.195+55A>C (chr4-99949218-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.206

Publications

6 publications found

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]

H2AZ1 links:

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new If you want to explore the variant's impact on the transcript NM_002106.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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.195+55A>C		intron	N/A	NP_002097.1	P0C0S5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
H2AZ1	ENST00000296417.6	TSL:1 MANE Select	c.195+55A>C	intron	N/A	ENSP00000296417.5	P0C0S5
H2AZ1	ENST00000511348.1	TSL:1	n.711A>C	non_coding_transcript_exon	Exon 2 of 2
H2AZ1	ENST00000511319.5	TSL:1	n.720+55A>C	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.247

AC:

37419

AN:

151698

Hom.:

4762

Cov.:

show subpopulations

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.:

AF XY:

0.221

AC XY:

104611

AN XY:

472310

show subpopulations

African (AFR)

AF:

0.302

AC:

6622

AN:

21958

American (AMR)

AF:

0.214

AC:

7039

AN:

32946

Ashkenazi Jewish (ASJ)

AF:

0.345

AC:

6858

AN:

19854

East Asian (EAS)

AF:

0.204

AC:

7472

AN:

36694

South Asian (SAS)

AF:

0.155

AC:

10824

AN:

69694

European-Finnish (FIN)

AF:

0.248

AC:

12665

AN:

51046

Middle Eastern (MID)

AF:

0.271

AC:

1187

AN:

4388

European-Non Finnish (NFE)

AF:

0.223

AC:

142351

AN:

639496

Other (OTH)

AF:

0.232

AC:

9607

AN:

41476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

8224

16447

24671

32894

41118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3724

7448

11172

14896

18620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.247

AC:

37439

AN:

151816

Hom.:

4765

Cov.:

AF XY:

0.242

AC XY:

17926

AN XY:

74194

show subpopulations

African (AFR)

AF:

0.294

AC:

12160

AN:

41384

American (AMR)

AF:

0.219

AC:

3338

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.347

AC:

1205

AN:

3472

East Asian (EAS)

AF:

0.146

AC:

750

AN:

5128

South Asian (SAS)

AF:

0.157

AC:

756

AN:

4820

European-Finnish (FIN)

AF:

0.242

AC:

2556

AN:

10546

Middle Eastern (MID)

AF:

0.216

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.233

AC:

15816

AN:

67938

Other (OTH)

AF:

0.260

AC:

545

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1408

2815

4223

5630

7038

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

392

784

1176

1568

1960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

(source)

DANN

Benign

0.54

PhyloP100

-0.21

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over