rs2294851

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018194.6(HHAT):c.545G>A(p.Ser182Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,613,550 control chromosomes in the GnomAD database, including 18,017 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1301 hom., cov: 32)

Exomes 𝑓: 0.15 ( 16716 hom. )

Consequence

HHAT
NM_018194.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 8.99

Publications

32 publications found

Variant links:

Genes affected

HHAT (HGNC:18270): (hedgehog acyltransferase) 'Skinny hedgehog' (SKI1) encodes an enzyme that acts within the secretory pathway to catalyze amino-terminal palmitoylation of 'hedgehog' (see MIM 600725).[supplied by OMIM, Jul 2002]

HHAT Gene-Disease associations (from GenCC):

chondrodysplasia-pseudohermaphroditism syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)

HHAT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021119118).

BP6

Variant 1-210404540-G-A is Benign according to our data. Variant chr1-210404540-G-A is described in ClinVar as Benign. ClinVar VariationId is 1587713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HHAT	NM_018194.6 link	c.545G>A	p.Ser182Asn	missense_variant	Exon 6 of 12	ENST00000261458.8	NP_060664.2	Q5VTY9-1B7Z5N1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HHAT	ENST00000261458.8 link	c.545G>A	p.Ser182Asn	missense_variant	Exon 6 of 12	2	NM_018194.6	ENSP00000261458.3		Q5VTY9-1

Frequencies

GnomAD3 genomes

AF:

0.115

AC:

17526

AN:

152146

Hom.:

1298

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0293

Gnomad AMI

AF:

0.112

Gnomad AMR

AF:

0.169

Gnomad ASJ

AF:

0.115

Gnomad EAS

AF:

0.259

Gnomad SAS

AF:

0.124

Gnomad FIN

AF:

0.130

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.141

Gnomad OTH

AF:

0.121

GnomAD2 exomes

AF:

0.149

AC:

37569

AN:

251358

AF XY:

0.146

show subpopulations

Gnomad AFR exome

AF:

0.0242

Gnomad AMR exome

AF:

0.219

Gnomad ASJ exome

AF:

0.109

Gnomad EAS exome

AF:

0.275

Gnomad FIN exome

AF:

0.132

Gnomad NFE exome

AF:

0.143

Gnomad OTH exome

AF:

0.135

GnomAD4 exome

AF:

0.147

AC:

214164

AN:

1461286

Hom.:

16716

Cov.:

AF XY:

0.145

AC XY:

105434

AN XY:

726952

show subpopulations

African (AFR)

AF:

0.0211

AC:

707

AN:

33472

American (AMR)

AF:

0.210

AC:

9396

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

2986

AN:

26132

East Asian (EAS)

AF:

0.255

AC:

10115

AN:

39700

South Asian (SAS)

AF:

0.116

AC:

9976

AN:

86236

European-Finnish (FIN)

AF:

0.135

AC:

7207

AN:

53408

Middle Eastern (MID)

AF:

0.0750

AC:

421

AN:

5616

European-Non Finnish (NFE)

AF:

0.149

AC:

165191

AN:

1111638

Other (OTH)

AF:

0.135

AC:

8165

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

9159

18318

27478

36637

45796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6062

12124

18186

24248

30310

<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:

0.115

AC:

17525

AN:

152264

Hom.:

1301

Cov.:

AF XY:

0.117

AC XY:

8690

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0292

AC:

1213

AN:

41568

American (AMR)

AF:

0.170

AC:

2596

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

399

AN:

3470

East Asian (EAS)

AF:

0.259

AC:

1338

AN:

5166

South Asian (SAS)

AF:

0.123

AC:

595

AN:

4830

European-Finnish (FIN)

AF:

0.130

AC:

1379

AN:

10590

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.141

AC:

9608

AN:

68022

Other (OTH)

AF:

0.121

AC:

255

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

766

1532

2298

3064

3830

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

204

408

612

816

1020

<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:

0.132

Hom.:

3334

Bravo

AF:

0.116

TwinsUK

AF:

0.155

AC:

574

ALSPAC

AF:

0.152

AC:

585

ESP6500AA

AF:

0.0295

AC:

130

ESP6500EA

AF:

0.143

AC:

1231

ExAC

AF:

0.144

AC:

17471

Asia WGS

AF:

0.173

AC:

600

AN:

3478

EpiCase

AF:

0.137

EpiControl

AF:

0.138

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Thalidomide response

Other:1

Rare Diseases Genetics and Genomics, Islamia College Peshawar

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:research

this variant was associated with non-response to thalidomide (not achieving transfusion independence) non responsive

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.;.;D;D;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.64

T;T;T;.;.;T

MetaRNN

Benign

0.0021

T;T;T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

3.0

M;.;.;M;M;.

PhyloP100

9.0

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.4

N;N;N;N;N;N

REVEL

Benign

0.24

Sift

Uncertain

0.015

D;D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D;D

Polyphen

1.0

D;.;.;D;D;.

Vest4

0.47

MPC

0.51

ClinPred

0.019

GERP RS

5.5

Varity_R

0.60

gMVP

0.89

Mutation Taster

=14/86

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over