NM_018194.6:c.51C>G

Variant names:

• chr1-210349026-C-G
• rs141741088
• NM_018194.6:c.51C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018194.6(HHAT):​c.51C>G​(p.Phe17Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F17F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HHAT NM_018194.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• Publications: 1 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, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018194.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HHAT	NM_018194.6	MANE Select	c.51C>G	p.Phe17Leu	missense	Exon 2 of 12	NP_060664.2	Q5VTY9-1
	HHAT	NM_001122834.4		c.51C>G	p.Phe17Leu	missense	Exon 2 of 12	NP_001116306.1	Q5VTY9-1
	HHAT	NM_001170580.3		c.51C>G	p.Phe17Leu	missense	Exon 2 of 12	NP_001164051.1	Q5VTY9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HHAT	ENST00000261458.8	TSL:2 MANE Select	c.51C>G	p.Phe17Leu	missense	Exon 2 of 12	ENSP00000261458.3	Q5VTY9-1
	HHAT	ENST00000367010.5	TSL:2	c.51C>G	p.Phe17Leu	missense	Exon 2 of 12	ENSP00000355977.1	Q5VTY9-1
	HHAT	ENST00000413764.6	TSL:5	c.51C>G	p.Phe17Leu	missense	Exon 2 of 12	ENSP00000416845.2	Q5VTY9-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251368 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461830 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000888178), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

African (AFR) AF: 0.00 AC: 0 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0099	T
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.3
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.13
Sift	Benign	0.15	T
Sift4G	Benign	1.0	T
Polyphen		0.33	B
Vest4		0.74
MutPred		0.49		Loss of helix (P = 0.0167)
MVP		0.54
ClinPred		0.40	T
GERP RS		5.0
Varity_R		0.091
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs141741088; hg19: chr1-210522370;