rs1596435748

Variant names:

• chr5-141625208-C-A
• rs1596435748
• NM_003883.4:c.1217G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-141625208-C-A
• chr5-141625208-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003883.4(HDAC3):​c.1217G>T​(p.Arg406Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000069 in 1,449,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R406K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HDAC3 NM_003883.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.18
• Publications: 0 publications found

Genes affected

HDAC3 (HGNC:4854): (histone deacetylase 3) 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 the histone deacetylase/acuc/apha family. It has histone deacetylase activity and represses transcription when tethered to a promoter. It may participate in the regulation of transcription through its binding with the zinc-finger transcription factor YY1. This protein can also down-regulate p53 function and thus modulate cell growth and apoptosis. This gene is regarded as a potential tumor suppressor gene. [provided by RefSeq, Jul 2008]

HDAC3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ENSG00000228737 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003883.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC3	NM_003883.4	MANE Select	c.1217G>T	p.Arg406Met	missense splice_region	Exon 14 of 15	NP_003874.2
	HDAC3	NM_001355039.2		c.1217G>T	p.Arg406Met	missense	Exon 14 of 14	NP_001341968.1
	HDAC3	NM_001355040.2		c.758G>T	p.Arg253Met	missense splice_region	Exon 12 of 13	NP_001341969.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC3	ENST00000305264.8	TSL:1 MANE Select	c.1217G>T	p.Arg406Met	missense splice_region	Exon 14 of 15	ENSP00000302967.3	O15379-1
	HDAC3	ENST00000469550.6	TSL:1	n.1290G>T		splice_region non_coding_transcript_exon	Exon 12 of 13
	HDAC3	ENST00000937593.1		c.1241G>T	p.Arg414Met	missense splice_region	Exon 14 of 15	ENSP00000607652.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449322 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 720714

African (AFR) AF: 0.00 AC: 0 AN: 32790

American (AMR) AF: 0.00 AC: 0 AN: 40644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25642

East Asian (EAS) AF: 0.00 AC: 0 AN: 39486

South Asian (SAS) AF: 0.00 AC: 0 AN: 83746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5260

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108550

Other (OTH) AF: 0.00 AC: 0 AN: 59834

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	31
DANN	Benign	0.89
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.55	N
PhyloP100		7.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.25
Sift	Benign	0.12	T
Sift4G	Uncertain	0.056	T
Polyphen		0.040	B
Vest4		0.57
MutPred		0.25		Loss of glycosylation at S405 (P = 0.0416)
MVP		0.83
MPC		1.3
ClinPred		0.75	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.66
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1596435748; hg19: chr5-141004775;