2-239053442-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.3230+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,610,110 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (5 hom.)
• Consequence: HDAC4 NM_001378414.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.178

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=-0.87).
• BP6: Variant 2-239053442-G-A is Benign according to our data. Variant chr2-239053442-G-A is described in ClinVar as [Benign]. Clinvar id is 2887533.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00109 (166/152326) while in subpopulation NFE AF= 0.00193 (131/68024). AF 95% confidence interval is 0.00166. There are 0 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 166 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC4	NM_001378414.1	c.3230+18C>T		intron_variant		ENST00000543185.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC4	ENST00000543185.6	c.3230+18C>T		intron_variant		5	NM_001378414.1	A1
HDAC4	ENST00000345617.7	c.3215+18C>T		intron_variant		1		P4
HDAC4	ENST00000430200.1	c.487+18C>T		intron_variant		3
HDAC4	ENST00000690129.1	n.1244+18C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00110 AC: 272 AN: 248274 Hom.: 0 AF XY: 0.000974 AC XY: 131 AN XY: 134444

Gnomad AFR exome AF: 0.000872

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.000807

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000659

Gnomad FIN exome AF: 0.000749

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.00172 AC: 2503 AN: 1457784 Hom.: 5 Cov.: 32 AF XY: 0.00161 AC XY: 1168 AN XY: 724678

Gnomad4 AFR exome AF: 0.000718

Gnomad4 AMR exome AF: 0.000292

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.000761

Gnomad4 NFE exome AF: 0.00209

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.000994 AC XY: 74 AN XY: 74484

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00193

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.29
Dann	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs200713014; hg19: chr2-239975138;