1-210329023-C-G

Variant names:

• chr1-210329023-C-G
• NM_018194.6:c.-125C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001170587.3(HHAT):​c.13C>G​(p.Leu5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HHAT NM_001170587.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35
• Publications: 0 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)

ENSG00000310145 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10618296).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001170587.3. 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.-125C>G		5_prime_UTR	Exon 1 of 12	NP_060664.2	Q5VTY9-1
	HHAT	NM_001170587.3		c.13C>G	p.Leu5Val	missense	Exon 1 of 11	NP_001164058.1	Q5VTY9-7
	HHAT	NM_001170588.3		c.-125C>G		5_prime_UTR	Exon 1 of 11	NP_001164059.1	Q5VTY9-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HHAT	ENST00000261458.8	TSL:2 MANE Select	c.-125C>G		5_prime_UTR	Exon 1 of 12	ENSP00000261458.3	Q5VTY9-1
	HHAT	ENST00000545154.5	TSL:2	c.13C>G	p.Leu5Val	missense	Exon 1 of 11	ENSP00000438468.1	Q5VTY9-7
	HHAT	ENST00000537898.5	TSL:2	c.-125C>G		5_prime_UTR	Exon 1 of 11	ENSP00000442625.1	Q5VTY9-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Uncertain	1.0
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.3
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.025
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.14
MutPred		0.20		Gain of MoRF binding (P = 0.0911)
MVP		0.27
MPC		0.11
ClinPred		0.67	D
GERP RS		1.8
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.14
Mutation Taster		=97/3	polymorphism

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

hg19: chr1-210502367;