X-72351739-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_018486.3(HDAC8):c.1105A>G(p.Ile369Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000644 in 1,087,108 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000064 (0 hom. 3 hem.)
• Consequence: HDAC8 NM_018486.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.50

Genes affected

HDAC8 (HGNC:13315): (histone deacetylase 8) 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 I of the histone deacetylase family. It catalyzes the deacetylation of lysine residues in the histone N-terminal tails and represses transcription in large multiprotein complexes with transcriptional co-repressors. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.136504).
• BP6: Variant X-72351739-T-C is Benign according to our data. Variant chrX-72351739-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2172666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC8	NM_018486.3	c.1105A>G	p.Ile369Val	missense_variant	10/11	ENST00000373573.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC8	ENST00000373573.9	c.1105A>G	p.Ile369Val	missense_variant	10/11	1	NM_018486.3	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000110 AC: 2 AN: 181680 Hom.: 0 AF XY: 0.0000151 AC XY: 1 AN XY: 66336

Gnomad AFR exome AF: 0.0000764

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000644 AC: 7 AN: 1087108 Hom.: 0 Cov.: 27 AF XY: 0.00000849 AC XY: 3 AN XY: 353328

Gnomad4 AFR exome AF: 0.0000382

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: 0.00000721

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cornelia de Lange syndrome 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Apr 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	19
Dann	Benign	0.80
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.68	T;T;T;T;T;T;T;T;.;T;T;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
Polyphen		0.0	.;.;B;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.30, 0.28
MutPred		0.62		Loss of stability (P = 0.0838);.;Loss of stability (P = 0.0838);Loss of stability (P = 0.0838);Loss of stability (P = 0.0838);.;.;.;Loss of stability (P = 0.0838);.;Loss of stability (P = 0.0838);.;Loss of stability (P = 0.0838);.;
MVP		0.61
MPC		0.84
ClinPred		0.085	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.87

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: rs1555948950; hg19: chrX-71571589;