2-239053021-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001378414.1(HDAC4):c.*76C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,561,228 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (45 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (38 hom.)
• Consequence: HDAC4 NM_001378414.1 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.41

Genes affected

HDAC4 (HGNC:14063): (histone deacetylase 4) Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to class II of the histone deacetylase/acuc/apha family. It possesses histone deacetylase activity and represses transcription when tethered to a promoter. This protein does not bind DNA directly, but through transcription factors MEF2C and MEF2D. It seems to interact in a multiprotein complex with RbAp48 and HDAC3. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 2-239053021-G-A is Benign according to our data. Variant chr2-239053021-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1209358.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0117 (1786/152368) while in subpopulation AFR AF= 0.0412 (1713/41582). AF 95% confidence interval is 0.0396. There are 45 homozygotes in gnomad4. There are 855 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1781 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC4	NM_001378414.1	c.*76C>T		3_prime_UTR_variant	27/27	ENST00000543185.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC4	ENST00000543185.6	c.*76C>T		3_prime_UTR_variant	27/27	5	NM_001378414.1	A1
HDAC4	ENST00000345617.7	c.*76C>T		3_prime_UTR_variant	27/27	1		P4
HDAC4	ENST00000690129.1	n.1360C>T		non_coding_transcript_exon_variant	10/10
HDAC4	ENST00000430200.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1781 AN: 152250 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00132 AC: 1854 AN: 1408860 Hom.: 38 Cov.: 24 AF XY: 0.00114 AC XY: 805 AN XY: 704002

Gnomad4 AFR exome AF: 0.0464

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.0000388

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000164

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000479

Gnomad4 OTH exome AF: 0.00313

GnomAD4 genome AF: 0.0117 AC: 1786 AN: 152368 Hom.: 45 Cov.: 33 AF XY: 0.0115 AC XY: 855 AN XY: 74512

Gnomad4 AFR AF: 0.0412

Gnomad4 AMR AF: 0.00287

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00141 Hom.: 0

Bravo AF: 0.0133

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 08, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	11
Dann	Benign	0.88

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: rs13390561; hg19: chr2-239974717; COSMIC: COSV61862706; COSMIC: COSV61862706;