2-239053235-C-T

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.3231-99G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00564 in 1,491,208 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0060 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (39 hom.)
• Consequence: HDAC4 NM_001378414.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.491

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=-0.98).
• BP6: Variant 2-239053235-C-T is Benign according to our data. Variant chr2-239053235-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1208308.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00596 (908/152310) while in subpopulation AMR AF= 0.00634 (97/15304). AF 95% confidence interval is 0.00532. There are 12 homozygotes in gnomad4. There are 546 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 909 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC4	NM_001378414.1	c.3231-99G>A		intron_variant		ENST00000543185.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC4	ENST00000543185.6	c.3231-99G>A		intron_variant		5	NM_001378414.1	A1
HDAC4	ENST00000345617.7	c.3216-99G>A		intron_variant		1		P4
HDAC4	ENST00000430200.1	c.488-99G>A		intron_variant		3
HDAC4	ENST00000690129.1	n.1245-99G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00597 AC: 909 AN: 152192 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0348

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00556

Gnomad OTH AF: 0.00573

GnomAD4 exome AF: 0.00560 AC: 7500 AN: 1338898 Hom.: 39 AF XY: 0.00555 AC XY: 3706 AN XY: 668272

Gnomad4 AFR exome AF: 0.000849

Gnomad4 AMR exome AF: 0.00386

Gnomad4 ASJ exome AF: 0.00392

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00184

Gnomad4 FIN exome AF: 0.0281

Gnomad4 NFE exome AF: 0.00529

Gnomad4 OTH exome AF: 0.00533

GnomAD4 genome AF: 0.00596 AC: 908 AN: 152310 Hom.: 12 Cov.: 33 AF XY: 0.00733 AC XY: 546 AN XY: 74474

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.0348

Gnomad4 NFE AF: 0.00554

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00556 Hom.: 0

Bravo AF: 0.00363

Asia WGS AF: 0.000577 AC: 2 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

Feb 21, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.39
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs190924205; hg19: chr2-239974931;