2-239053510-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001378414.1(HDAC4):c.3180G>A(p.Thr1060=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000366 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: HDAC4 NM_001378414.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -6.43

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-239053510-C-T is Benign according to our data. Variant chr2-239053510-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 707442.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-6.43 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000387 (59/152344) while in subpopulation NFE AF= 0.000529 (36/68030). AF 95% confidence interval is 0.000392. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC4	NM_001378414.1	c.3180G>A	p.Thr1060=	synonymous_variant	26/27	ENST00000543185.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC4	ENST00000543185.6	c.3180G>A	p.Thr1060=	synonymous_variant	26/27	5	NM_001378414.1	A1
HDAC4	ENST00000345617.7	c.3165G>A	p.Thr1055=	synonymous_variant	26/27	1		P4
HDAC4	ENST00000430200.1	c.438G>A	p.Thr146=	synonymous_variant	3/4	3
HDAC4	ENST00000690129.1	n.1194G>A		non_coding_transcript_exon_variant	9/10

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000271 AC: 68 AN: 250672 Hom.: 0 AF XY: 0.000250 AC XY: 34 AN XY: 135730

Gnomad AFR exome AF: 0.000371

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000486

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000364 AC: 532 AN: 1461462 Hom.: 0 Cov.: 32 AF XY: 0.000353 AC XY: 257 AN XY: 727046

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000565

Gnomad4 NFE exome AF: 0.000438

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152344 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74484

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000366 Hom.: 0

Bravo AF: 0.000397

EpiCase AF: 0.000436

EpiControl AF: 0.000415

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

Invitae

Jul 12, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	2.5
Dann	Benign	0.89

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: rs114003127; hg19: chr2-239975206; COSMIC: COSV61859867; COSMIC: COSV61859867;