Genetic Variant HDAC8:c.1111+16C>T (chrX-72351717-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The NM_018486.3(HDAC8):c.1111+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000258 in 1,162,597 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000027 ( 0 hom. 10 hem. )

Consequence

HDAC8
NM_018486.3 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.816

Publications

0 publications found

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]

HDAC8 Gene-Disease associations (from GenCC):

Cornelia de Lange syndrome
Inheritance: XL, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Cornelia de Lange syndrome 5
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
Wilson-Turner syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

HDAC8 links:

ENSG00000285547 (HGNC:):

ENSG00000285547 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13712537).

BP6

Variant X-72351717-G-A is Benign according to our data. Variant chrX-72351717-G-A is described in ClinVar as Benign. ClinVar VariationId is 1633109.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000267 (28/1050096) while in subpopulation AMR AF = 0.000257 (9/34979). AF 95% confidence interval is 0.000133. There are 0 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 28 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018486.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HDAC8	NM_018486.3	MANE Select	c.1111+16C>T	intron	N/A	NP_060956.1	Q9BY41-1
HDAC8	NM_001410725.1		c.1111+16C>T	intron	N/A	NP_001397654.1	A0A3B3IS68
HDAC8	NM_001410727.1		c.1033+16C>T	intron	N/A	NP_001397656.1	A6NFW1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HDAC8	ENST00000373573.9	TSL:1 MANE Select	c.1111+16C>T		intron	N/A	ENSP00000362674.3	Q9BY41-1
ENSG00000285547	ENST00000648922.1		c.1111+16C>T		intron	N/A	ENSP00000497072.1	A0A3B3IRV1
HDAC8	ENST00000373568.7	TSL:5	c.1127C>T	p.Ser376Leu	missense	Exon 10 of 10	ENSP00000362669.3	A6NGJ7

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112501

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000624

AC:

AN:

176308

AF XY:

0.0000488

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000374

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:

0.000228

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1050096

Hom.:

Cov.:

AF XY:

0.0000306

AC XY:

AN XY:

326412

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25463

American (AMR)

AF:

0.000257

AC:

AN:

34979

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19075

East Asian (EAS)

AF:

0.00

AC:

AN:

29962

South Asian (SAS)

AF:

0.00

AC:

AN:

52524

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40407

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3988

European-Non Finnish (NFE)

AF:

0.0000163

AC:

AN:

799187

Other (OTH)

AF:

0.000135

AC:

AN:

44511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112501

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34657

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30926

American (AMR)

AF:

0.00

AC:

AN:

10701

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3577

South Asian (SAS)

AF:

0.00

AC:

AN:

2739

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000375

AC:

AN:

53282

Other (OTH)

AF:

0.00

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cornelia de Lange syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_noAF

Benign

-0.76

CADD

Benign

7.2

(source)

DANN

Benign

0.75

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.32

MetaRNN

Benign

0.14

PhyloP100

0.82

GERP RS

1.4

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over