Genetic Variant HHAT:p.Met1? (chr1-210348976-A-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_018194.6(HHAT):c.1A>T(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HHAT
NM_018194.6 initiator_codon

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.67

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 64 codons. Genomic position: 210387498. Lost 0.128 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-210348976-A-T is Pathogenic according to our data. Variant chr1-210348976-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521737.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HHAT	NM_018194.6 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 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.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 12	2	NM_018194.6	ENSP00000261458.3		Q5VTY9-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461744

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Jun 16, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lines of evidence used in support of classification: CANDIDATE: Alteration(s) of Potential Clinical Relevance Detected -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.063

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.63

DEOGEN2

Benign

0.20

.;T;.;T;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.90

D;D;D;.;.

M_CAP

Benign

0.0089

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Benign

-1.1

PROVEAN

Benign

-0.57

N;N;N;N;N

REVEL

Benign

0.20

Sift

Pathogenic

0.0

D;D;T;D;D

Sift4G

Benign

0.084

T;T;T;T;T

Polyphen

0.068

.;B;.;B;B

Vest4

0.68

MutPred

1.0

Loss of disorder (P = 0.1734);Loss of disorder (P = 0.1734);Loss of disorder (P = 0.1734);Loss of disorder (P = 0.1734);Loss of disorder (P = 0.1734);

MVP

0.22

ClinPred

0.91

GERP RS

2.7

Varity_R

0.23

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