1-210362834-CTTT-CTT

Variant names:

• chr1-210362834-CT-C
• rs371568839
• NM_018194.6:c.92-7delT

Variant summary

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

The NM_018194.6(HHAT):​c.92-7delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0474 in 943,374 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.056 (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: Variant has high frequency in the SAS (0.0808) population. However there is too low homozygotes in high coverage region: (expected more than 530, got 0).

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.92-7delT		splice_region intron	N/A	NP_060664.2	Q5VTY9-1
	HHAT	NM_001170587.3		c.95-7delT		splice_region intron	N/A	NP_001164058.1	Q5VTY9-7
	HHAT	NM_001122834.4		c.92-7delT		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.92-17delT		intron	N/A	ENSP00000261458.3	Q5VTY9-1
	HHAT	ENST00000545154.5	TSL:2	c.95-17delT		intron	N/A	ENSP00000438468.1	Q5VTY9-7
	HHAT	ENST00000367010.5	TSL:2	c.92-17delT		intron	N/A	ENSP00000355977.1	Q5VTY9-1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 52 AN: 146380 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000688

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000594

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00140

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000393

Gnomad OTH AF: 0.000502

GnomAD2 exomes AF: 0.138 AC: 11322 AN: 82276 AF XY: 0.141

Gnomad AFR exome AF: 0.0832

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.142

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.0561 AC: 44686 AN: 796932 Hom.: 0 Cov.: 24 AF XY: 0.0571 AC XY: 22385 AN XY: 392226

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

African (AFR) AF: 0.0539 AC: 1013 AN: 18780

American (AMR) AF: 0.0829 AC: 2007 AN: 24202

Ashkenazi Jewish (ASJ) AF: 0.0736 AC: 913 AN: 12410

East Asian (EAS) AF: 0.0584 AC: 1092 AN: 18710

South Asian (SAS) AF: 0.0830 AC: 3638 AN: 43826

European-Finnish (FIN) AF: 0.0604 AC: 1705 AN: 28244

Middle Eastern (MID) AF: 0.0391 AC: 143 AN: 3660

European-Non Finnish (NFE) AF: 0.0526 AC: 32330 AN: 614914

Other (OTH) AF: 0.0573 AC: 1845 AN: 32186

⚠️ 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 AF: 0.000355 AC: 52 AN: 146442 Hom.: 0 Cov.: 32 AF XY: 0.000393 AC XY: 28 AN XY: 71216

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

African (AFR) AF: 0.000199 AC: 8 AN: 40216

American (AMR) AF: 0.0000687 AC: 1 AN: 14546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3380

East Asian (EAS) AF: 0.000596 AC: 3 AN: 5036

South Asian (SAS) AF: 0.00 AC: 0 AN: 4614

European-Finnish (FIN) AF: 0.00140 AC: 13 AN: 9286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000393 AC: 26 AN: 66166

Other (OTH) AF: 0.000497 AC: 1 AN: 2012

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0710 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.25
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs371568839; hg19: chr1-210536178; COSMIC: COSV54795725; COSMIC: COSV54795725;