X-48802995-G-C

Position:

chrX-48802995-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_006044.4(HDAC6):c.218G>C(p.Gly73Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,209,149 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 53 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 (no stars).

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., 20 hem., cov: 23)

Exomes 𝑓: 0.000092 ( 0 hom. 33 hem. )

Consequence

HDAC6
NM_006044.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.0590

Variant links:

Genes affected

HDAC6 (HGNC:14064): (histone deacetylase 6) 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 II of the histone deacetylase/acuc/apha family. It contains an internal duplication of two catalytic domains which appear to function independently of each other. This protein possesses histone deacetylase activity and represses transcription. [provided by RefSeq, Jul 2008]

HDAC6 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HDAC6. . Gene score misZ 3.2915 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked dominant chondrodysplasia, Chassaing-Lacombe type.

BP4

Computational evidence support a benign effect (MetaRNN=0.0051502883).

BP6

Variant X-48802995-G-C is Benign according to our data. Variant chrX-48802995-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1050458.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Hemizygotes in GnomAd4 at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC6	NM_006044.4 link	c.218G>C	p.Gly73Ala	missense_variant	3/29	ENST00000334136.11	NP_006035.2	Q9UBN7-1A0A024QZ26Q9NSW6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC6	ENST00000334136.11 link	c.218G>C	p.Gly73Ala	missense_variant	3/29	1	NM_006044.4	ENSP00000334061.5		Q9UBN7-1

Frequencies

GnomAD3 genomes

AF:

0.000641

AC:

AN:

112355

Hom.:

Cov.:

AF XY:

0.000406

AC XY:

AN XY:

34507

show subpopulations

Gnomad AFR

AF:

0.00220

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000188

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:

0.00132

GnomAD3 exomes

AF:

0.000184

AC:

AN:

178995

Hom.:

AF XY:

0.000141

AC XY:

AN XY:

63699

show subpopulations

Gnomad AFR exome

AF:

0.00241

Gnomad AMR exome

AF:

0.0000369

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000921

AC:

101

AN:

1096742

Hom.:

Cov.:

AF XY:

0.0000911

AC XY:

AN XY:

362190

show subpopulations

Gnomad4 AFR exome

AF:

0.00303

Gnomad4 AMR exome

AF:

0.0000855

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000743

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000261

GnomAD4 genome

AF:

0.000703

AC:

AN:

112407

Hom.:

Cov.:

AF XY:

0.000579

AC XY:

AN XY:

34569

show subpopulations

Gnomad4 AFR

AF:

0.00242

Gnomad4 AMR

AF:

0.000188

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:

0.00130

Alfa

AF:

0.000201

Hom.:

Bravo

AF:

0.000861

ESP6500AA

AF:

0.00417

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000280

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The HDAC6 p.Gly73Ala variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs145349858) and LOVD 3.0. The variant was identified in control databases in 39 of 200969 chromosomes (12 hemizygous) at a frequency of 0.0001941 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 37 of 18780 chromosomes (freq: 0.00197), South Asian in 1 of 18365 chromosomes (freq: 0.000054) and Latino in 1 of 27713 chromosomes (freq: 0.000036), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), or Other populations. The p.Gly73 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.8

DANN

Benign

0.67

DEOGEN2

Benign

0.13

.;T;T;T;.;T;T;.;.;T;T;.;.;.;T;.

FATHMM_MKL

Benign

0.22

LIST_S2

Uncertain

0.86

D;.;T;.;.;.;.;.;.;.;T;D;T;D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.0052

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

.;.;.;L;.;L;L;.;.;L;L;.;.;.;.;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.1

N;N;N;N;.;N;N;.;.;.;.;N;.;.;N;N

REVEL

Benign

0.042

Sift

Benign

0.28

T;T;T;T;.;T;T;.;.;.;.;T;.;.;T;T

Sift4G

Benign

0.41

T;T;T;T;.;T;T;.;.;.;.;T;.;.;T;T

Polyphen

0.15, 0.34

.;.;.;B;B;B;B;B;.;B;B;B;.;.;.;.

Vest4

0.16, 0.14

MVP

0.68

MPC

1.1

ClinPred

0.0027

GERP RS

-0.56

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.1

Varity_R

0.078

gMVP

0.43

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over