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GeneBe

X-72351762-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_018486.3(HDAC8):c.1082G>A(p.Arg361Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,208,029 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)
Exomes 𝑓: 0.000022 ( 0 hom. 3 hem. )

Consequence

HDAC8
NM_018486.3 missense

Scores

1
8

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.69
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.057283998).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant X-72351762-C-T is Benign according to our data. Variant chrX-72351762-C-T is described in ClinVar as [Benign]. Clinvar id is 1662859.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000219 (24/1095592) while in subpopulation AMR AF= 0.000426 (15/35187). AF 95% confidence interval is 0.000263. There are 0 homozygotes in gnomad4_exome. There are 3 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Hemizygotes in GnomAdExome at 3 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HDAC8NM_018486.3 linkuse as main transcriptc.1082G>A p.Arg361Gln missense_variant 10/11 ENST00000373573.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HDAC8ENST00000373573.9 linkuse as main transcriptc.1082G>A p.Arg361Gln missense_variant 10/111 NM_018486.3 P4Q9BY41-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000267
AC:
3
AN:
112388
Hom.:
0
Cov.:
23
AF XY:
0.0000289
AC XY:
1
AN XY:
34552
show subpopulations
Gnomad AFR
AF:
0.0000647
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000939
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000876
AC:
16
AN:
182559
Hom.:
0
AF XY:
0.0000447
AC XY:
3
AN XY:
67149
show subpopulations
Gnomad AFR exome
AF:
0.000152
Gnomad AMR exome
AF:
0.000475
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000529
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000219
AC:
24
AN:
1095592
Hom.:
0
Cov.:
28
AF XY:
0.00000831
AC XY:
3
AN XY:
361034
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000426
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000185
Gnomad4 FIN exome
AF:
0.0000247
Gnomad4 NFE exome
AF:
0.00000476
Gnomad4 OTH exome
AF:
0.0000435
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000267
AC:
3
AN:
112437
Hom.:
0
Cov.:
23
AF XY:
0.0000289
AC XY:
1
AN XY:
34613
show subpopulations
Gnomad4 AFR
AF:
0.0000646
Gnomad4 AMR
AF:
0.0000938
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000453
ExAC
?
    Exome Aggregation Consortium database
AF:
0.0000741
AC:
9

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cornelia de Lange syndrome 5 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeDec 11, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.085
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.38
Cadd
Benign
18
Dann
Uncertain
1.0
FATHMM_MKL
Benign
0.48
N
LIST_S2
Benign
0.32
T
M_CAP
Benign
0.043
D
MetaRNN
Benign
0.057
T
MutationTaster
Benign
0.90
D;D;D;D
ClinPred
0.040
T
GERP RS
3.0

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs781862582; hg19: chrX-71571612; COSMIC: COSV65265941; COSMIC: COSV65265941; API