1-210362834-CTTT-CTTTTTT

Variant names:

• chr1-210362834-C-CTTT
• rs371568839
• NM_018194.6:c.92-9_92-7dupTTT

Variant summary

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

The NM_018194.6(HHAT):​c.92-9_92-7dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,065,024 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: HHAT NM_018194.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.250
• 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)

ENSG00000287354 (HGNC:):

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.92-9_92-7dupTTT		splice_region intron	N/A	NP_060664.2	Q5VTY9-1
	HHAT	NM_001170587.3		c.95-9_95-7dupTTT		splice_region intron	N/A	NP_001164058.1	Q5VTY9-7
	HHAT	NM_001122834.4		c.92-9_92-7dupTTT		splice_region intron	N/A	NP_001116306.1	Q5VTY9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HHAT	ENST00000261458.8	TSL:2 MANE Select	c.92-18_92-17insTTT		intron	N/A	ENSP00000261458.3	Q5VTY9-1
	HHAT	ENST00000545154.5	TSL:2	c.95-18_95-17insTTT		intron	N/A	ENSP00000438468.1	Q5VTY9-7
	HHAT	ENST00000367010.5	TSL:2	c.92-18_92-17insTTT		intron	N/A	ENSP00000355977.1	Q5VTY9-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 82276 AF XY: 0.00

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: 0.00000282 AC: 3 AN: 1065024 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 531566

⚠️ 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: 24792

American (AMR) AF: 0.00 AC: 0 AN: 33592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19054

East Asian (EAS) AF: 0.00 AC: 0 AN: 28952

South Asian (SAS) AF: 0.0000154 AC: 1 AN: 64918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4582

European-Non Finnish (NFE) AF: 0.00000248 AC: 2 AN: 805442

Other (OTH) AF: 0.00 AC: 0 AN: 44098

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.25

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs371568839; hg19: chr1-210536178;