Genetic Variant H2BC26:c.*3517T>A (chr1-228462027-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The ENST00000620438.2(H2BC26):c.*3517T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 152,528 control chromosomes in the GnomAD database, including 54 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 0.021 ( 51 hom., cov: 31)

Exomes 𝑓: 0.034 ( 3 hom. )

Consequence

H2BC26
ENST00000620438.2 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.07

Variant links:

Genes affected

H2BC26 (HGNC:20514): (H2B clustered histone 26) 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 is intronless and encodes a replication-dependent histone that is a member of the histone H2B family. Transcripts from this gene contain a palindromic termination element. [provided by RefSeq, Aug 2015]

H2BC26 links:

MIR4666A (HGNC:41750): (microRNA 4666a) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR4666A links:

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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=-0.88).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0214 (3227/150448) while in subpopulation EAS AF = 0.0447 (219/4902). AF 95% confidence interval is 0.0398. There are 51 homozygotes in GnomAd4. There are 1609 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 51 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect
MIR4666A	NR_039812.1 link	n.-47T>A	upstream_gene_variant
MIR4666A	unassigned_transcript_303	n.-56T>A	upstream_gene_variant
MIR4666A	unassigned_transcript_304	n.-98T>A	upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
H2BC26	ENST00000620438.2 link	c.*3517T>A	3_prime_UTR_variant	Exon 1 of 1	6	ENSP00000479284.1	Q8N257
H2BC26	ENST00000690378.1 link	n.1161T>A	non_coding_transcript_exon_variant	Exon 2 of 2
MIR4666A	ENST00000580160.1 link	n.-47T>A	upstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.0215

AC:

3231

AN:

150328

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0339

Gnomad AMI

AF:

0.0232

Gnomad AMR

AF:

0.0383

Gnomad ASJ

AF:

0.0212

Gnomad EAS

AF:

0.0446

Gnomad SAS

AF:

0.00603

Gnomad FIN

AF:

0.00745

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.0192

GnomAD2 exomes

AF:

0.00833

AC:

AN:

360

AF XY:

0.0147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00578

Gnomad OTH exome

AF:

0.100

GnomAD4 exome

AF:

0.0337

AC:

AN:

2080

Hom.:

Cov.:

AF XY:

0.0338

AC XY:

AN XY:

1036

show subpopulations

Gnomad4 AFR exome

AF:

0.0143

AC:

AN:

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

Gnomad4 EAS exome

AC:

AN:

Gnomad4 SAS exome

AF:

0.0116

AC:

AN:

Gnomad4 FIN exome

AC:

AN:

Gnomad4 NFE exome

AF:

0.00568

AC:

AN:

176

Gnomad4 Remaining exome

AF:

0.0444

AC:

AN:

180

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

<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:

0.0214

AC:

3227

AN:

150448

Hom.:

Cov.:

AF XY:

0.0219

AC XY:

1609

AN XY:

73480

show subpopulations

Gnomad4 AFR

AF:

0.0338

AC:

0.0337759

AN:

0.0337759

Gnomad4 AMR

AF:

0.0381

AC:

0.0381322

AN:

0.0381322

Gnomad4 ASJ

AF:

0.0212

AC:

0.0211594

AN:

0.0211594

Gnomad4 EAS

AF:

0.0447

AC:

0.0446756

AN:

0.0446756

Gnomad4 SAS

AF:

0.00603

AC:

0.00603448

AN:

0.00603448

Gnomad4 FIN

AF:

0.00745

AC:

0.00744986

AN:

0.00744986

Gnomad4 NFE

AF:

0.0117

AC:

0.01168

AN:

0.01168

Gnomad4 OTH

AF:

0.0190

AC:

0.0190476

AN:

0.0190476

Heterozygous variant carriers

152

304

457

609

761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0163

Hom.:

Bravo

AF:

0.0262

Asia WGS

AF:

0.0310

AC:

107

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

0.23

DANN

Benign

0.53

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over