5-141625208-C-T

Position:

• chr5-141625208-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003883.4(HDAC3):​c.1217G>A​(p.Arg406Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HDAC3 NM_003883.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.18

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, HDAC3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC3	NM_003883.4	c.1217G>A	p.Arg406Lys	missense_variant, splice_region_variant	14/15	ENST00000305264.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC3	ENST00000305264.8	c.1217G>A	p.Arg406Lys	missense_variant, splice_region_variant	14/15	1	NM_003883.4	P1
	ENST00000422040.2	n.77-639C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449322 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 720714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.072
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-0.14	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.15
Sift	Benign	0.82	T
Sift4G	Benign	0.41	T
Polyphen		0.18	B
Vest4		0.52
MutPred		0.32		Gain of ubiquitination at R406 (P = 0.0025);
MVP		0.57
MPC		1.2
ClinPred		0.85	D
GERP RS		5.3
Varity_R		0.23
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.78		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1596435748; hg19: chr5-141004775;