12-47788119-G-C

Variant names:

• chr12-47788119-G-C
• rs143706913
• NM_015401.5:c.2281C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS2

The NM_015401.5(HDAC7):​c.2281C>G​(p.Pro761Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,180 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HDAC7 NM_015401.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.79
• Publications: 2 publications found

Genes affected

HDAC7 (HGNC:14067): (histone deacetylase 7) 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 has sequence homology to members of the histone deacetylase family. This gene is orthologous to mouse HDAC7 gene whose protein promotes repression mediated via the transcriptional corepressor SMRT. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015401.5. 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
	HDAC7	NM_015401.5	MANE Select	c.2281C>G	p.Pro761Ala	missense	Exon 20 of 26	NP_056216.2	Q8WUI4-5
	HDAC7	NM_001368046.1		c.2323C>G	p.Pro775Ala	missense	Exon 20 of 26	NP_001354975.1
	HDAC7	NM_001308090.2		c.2230C>G	p.Pro744Ala	missense	Exon 19 of 25	NP_001295019.1	Q8WUI4-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC7	ENST00000080059.12	TSL:1 MANE Select	c.2281C>G	p.Pro761Ala	missense	Exon 20 of 26	ENSP00000080059.7	Q8WUI4-5
	HDAC7	ENST00000380610.8	TSL:2	c.2332C>G	p.Pro778Ala	missense	Exon 20 of 27	ENSP00000369984.4	J3KPH8
	HDAC7	ENST00000354334.7	TSL:1	c.2170C>G	p.Pro724Ala	missense	Exon 19 of 25	ENSP00000351326.3	Q8WUI4-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250522 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461180 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726840

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111642

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000306 Hom.: 3

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.056	T
Polyphen		0.014	B
Vest4		0.66
MutPred		0.63		Gain of catalytic residue at Q759 (P = 0.0044)
MVP		0.64
MPC		0.84
ClinPred		0.41	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.90
Mutation Taster		=59/41	polymorphism

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: rs143706913; hg19: chr12-48181902;