chr1-210404540-G-A

Variant names:

• chr1-210404540-G-A
• rs2294851
• NM_018194.6:c.545G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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 (★★).

• 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, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 8.99
• Publications: 32 publications found

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)

ACMG classification

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	c.545G>A	p.Ser182Asn	missense_variant	Exon 6 of 12	ENST00000261458.8	NP_060664.2

Ensembl

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

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

GnomAD2 exomes AF: 0.149 AC: 37569 AN: 251358 AF XY: 0.146

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

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

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

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: 40 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9608 AN: 68022

Other (OTH) AF: 0.121 AC: 255 AN: 2114

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:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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	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;.
PhyloP100		9.0
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
Mutation Taster		=14/86	polymorphism (auto)

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

Other links and lift over

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