chr2-239082174-G-A

Position:

• chr2-239082174-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378414.1(HDAC4):​c.2580C>T​(p.Pro860Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 1,613,816 control chromosomes in the GnomAD database, including 197,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20770 hom., cov: 33)
  • Exomes 𝑓: 0.49 (176246 hom.)
• Consequence: HDAC4 NM_001378414.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0730

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]

HDAC4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-239082174-G-A is Benign according to our data. Variant chr2-239082174-G-A is described in ClinVar as [Benign]. Clinvar id is 1174850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-239082174-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.073 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC4	NM_001378414.1	c.2580C>T	p.Pro860Pro	synonymous_variant	21/27	ENST00000543185.6	NP_001365343.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC4	ENST00000543185.6	c.2580C>T	p.Pro860Pro	synonymous_variant	21/27	5	NM_001378414.1	ENSP00000440481.3
HDAC4	ENST00000345617.7	c.2565C>T	p.Pro855Pro	synonymous_variant	21/27	1		ENSP00000264606.3
HDAC4	ENST00000487617.5	n.472C>T		non_coding_transcript_exon_variant	7/8	3
HDAC4	ENST00000690129.1	n.594C>T		non_coding_transcript_exon_variant	4/10

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78860 AN: 151966 Hom.: 20724 Cov.: 33

Gnomad AFR AF: 0.575

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.596

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.529

GnomAD3 exomes AF: 0.537 AC: 134954 AN: 251476 Hom.: 37567 AF XY: 0.533 AC XY: 72393 AN XY: 135914

Gnomad AFR exome AF: 0.566

Gnomad AMR exome AF: 0.687

Gnomad ASJ exome AF: 0.478

Gnomad EAS exome AF: 0.684

Gnomad SAS exome AF: 0.610

Gnomad FIN exome AF: 0.466

Gnomad NFE exome AF: 0.463

Gnomad OTH exome AF: 0.510

GnomAD4 exome AF: 0.487 AC: 711312 AN: 1461732 Hom.: 176246 Cov.: 47 AF XY: 0.489 AC XY: 355241 AN XY: 727182

Gnomad4 AFR exome AF: 0.574

Gnomad4 AMR exome AF: 0.679

Gnomad4 ASJ exome AF: 0.478

Gnomad4 EAS exome AF: 0.646

Gnomad4 SAS exome AF: 0.606

Gnomad4 FIN exome AF: 0.465

Gnomad4 NFE exome AF: 0.461

Gnomad4 OTH exome AF: 0.502

GnomAD4 genome AF: 0.519 AC: 78962 AN: 152084 Hom.: 20770 Cov.: 33 AF XY: 0.524 AC XY: 38962 AN XY: 74324

Gnomad4 AFR AF: 0.575

Gnomad4 AMR AF: 0.597

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.694

Gnomad4 SAS AF: 0.618

Gnomad4 FIN AF: 0.458

Gnomad4 NFE AF: 0.460

Gnomad4 OTH AF: 0.523

Alfa AF: 0.479 Hom.: 10771

Bravo AF: 0.534

Asia WGS AF: 0.620 AC: 2156 AN: 3478

EpiCase AF: 0.462

EpiControl AF: 0.464

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2018	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.1
DANN	Benign	0.91

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: rs1063639; hg19: chr2-240003870; COSMIC: COSV61872274; COSMIC: COSV61872274;