rs2294851

chr1-210404540-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1301 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16716 hom.)
• Consequence: HHAT NM_018194.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 8.99

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 1587713.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
HHAT	NM_018194.6	c.545G>A	p.Ser182Asn	missense_variant	6/12	ENST00000261458.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HHAT	ENST00000261458.8	c.545G>A	p.Ser182Asn	missense_variant	6/12	2	NM_018194.6	P1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17526 AN: 152146 Hom.: 1298 Cov.: 32

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

GnomAD3 exomes AF: 0.149 AC: 37569 AN: 251358 Hom.: 3218 AF XY: 0.146 AC XY: 19775 AN XY: 135840

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 SAS exome AF: 0.116

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.: 36 AF XY: 0.145 AC XY: 105434 AN XY: 726952

Gnomad4 AFR exome AF: 0.0211

Gnomad4 AMR exome AF: 0.210

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.255

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.149

Gnomad4 OTH exome AF: 0.135

GnomAD4 genome AF: 0.115 AC: 17525 AN: 152264 Hom.: 1301 Cov.: 32 AF XY: 0.117 AC XY: 8690 AN XY: 74440

Gnomad4 AFR AF: 0.0292

Gnomad4 AMR AF: 0.170

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.259

Gnomad4 SAS AF: 0.123

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.121

Alfa AF: 0.137 Hom.: 2322

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
Cadd	Pathogenic	26
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	D
LIST_S2	Benign	0.64	T;T;T;.;.;T
MetaRNN	Benign	0.0021	T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.0	M;.;.;M;M;.
MutationTaster	Benign	1.1e-7	P;P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.64	T
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	T
GERP RS		5.5
Varity_R		0.60
gMVP		0.89

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

Other links and lift over

dbSNP: rs2294851; hg19: chr1-210577884; COSMIC: COSV54793562;