rs1063639

Variant names:

• chr2-239082174-G-A
• rs1063639
• NM_001378414.1:c.2580C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-239082174-G-A
• chr2-239082174-G-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 27 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with central hypotonia and dysmorphic facies

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 2q37 microdeletion syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1174850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378414.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC4	NM_001378414.1	MANE Select	c.2580C>T	p.Pro860Pro	synonymous	Exon 21 of 27	NP_001365343.1
	HDAC4	NM_001378415.1		c.2580C>T	p.Pro860Pro	synonymous	Exon 21 of 27	NP_001365344.1
	HDAC4	NM_001378416.1		c.2565C>T	p.Pro855Pro	synonymous	Exon 21 of 27	NP_001365345.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC4	ENST00000543185.6	TSL:5 MANE Select	c.2580C>T	p.Pro860Pro	synonymous	Exon 21 of 27	ENSP00000440481.3
	HDAC4	ENST00000345617.7	TSL:1	c.2565C>T	p.Pro855Pro	synonymous	Exon 21 of 27	ENSP00000264606.3
	HDAC4	ENST00000487617.5	TSL:3	n.472C>T		non_coding_transcript_exon	Exon 7 of 8

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

GnomAD2 exomes AF: 0.537 AC: 134954 AN: 251476 AF XY: 0.533

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 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

African (AFR) AF: 0.574 AC: 19206 AN: 33478

American (AMR) AF: 0.679 AC: 30385 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 12481 AN: 26134

East Asian (EAS) AF: 0.646 AC: 25644 AN: 39700

South Asian (SAS) AF: 0.606 AC: 52310 AN: 86256

European-Finnish (FIN) AF: 0.465 AC: 24853 AN: 53406

Middle Eastern (MID) AF: 0.535 AC: 3083 AN: 5766

European-Non Finnish (NFE) AF: 0.461 AC: 513041 AN: 1111876

Other (OTH) AF: 0.502 AC: 30309 AN: 60392

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

African (AFR) AF: 0.575 AC: 23866 AN: 41494

American (AMR) AF: 0.597 AC: 9130 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1683 AN: 3466

East Asian (EAS) AF: 0.694 AC: 3564 AN: 5138

South Asian (SAS) AF: 0.618 AC: 2986 AN: 4828

European-Finnish (FIN) AF: 0.458 AC: 4841 AN: 10576

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.460 AC: 31251 AN: 67972

Other (OTH) AF: 0.523 AC: 1102 AN: 2106

Alfa AF: 0.484 Hom.: 34869

Bravo AF: 0.534

Asia WGS AF: 0.620 AC: 2156 AN: 3478

EpiCase AF: 0.462

EpiControl AF: 0.464

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.1
DANN	Benign	0.91
PhyloP100		0.073
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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