1-210362834-CTTT-CTTTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_018194.6(HHAT):​c.92-7dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.025 in 1,070,256 control chromosomes in the GnomAD database, including 8 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0063 (7 hom., cov: 32)
  • Exomes 𝑓: 0.028 (1 hom.)
• Consequence: HHAT NM_018194.6 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-210362834-C-CT is Benign according to our data. Variant chr1-210362834-C-CT is described in ClinVar as Benign. ClinVar VariationId is 1601509.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00625 (917/146694) while in subpopulation AFR AF = 0.0193 (775/40226). AF 95% confidence interval is 0.0181. There are 7 homozygotes in GnomAd4. There are 434 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.92-7dupT		splice_region intron	N/A	NP_060664.2	Q5VTY9-1
	HHAT	NM_001170587.3		c.95-7dupT		splice_region intron	N/A	NP_001164058.1	Q5VTY9-7
	HHAT	NM_001122834.4		c.92-7dupT		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_92-17insT		intron	N/A	ENSP00000261458.3	Q5VTY9-1
	HHAT	ENST00000545154.5	TSL:2	c.95-18_95-17insT		intron	N/A	ENSP00000438468.1	Q5VTY9-7
	HHAT	ENST00000367010.5	TSL:2	c.92-18_92-17insT		intron	N/A	ENSP00000355977.1	Q5VTY9-1

Frequencies

GnomAD3 genomes AF: 0.00626 AC: 918 AN: 146628 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00378

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000792

Gnomad SAS AF: 0.000432

Gnomad FIN AF: 0.000213

Gnomad MID AF: 0.00649

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00450

GnomAD2 exomes AF: 0.0535 AC: 4400 AN: 82276 AF XY: 0.0523

Gnomad AFR exome AF: 0.0929

Gnomad AMR exome AF: 0.0666

Gnomad ASJ exome AF: 0.0486

Gnomad EAS exome AF: 0.0539

Gnomad FIN exome AF: 0.0487

Gnomad NFE exome AF: 0.0441

Gnomad OTH exome AF: 0.0496

GnomAD4 exome AF: 0.0280 AC: 25879 AN: 923562 Hom.: 1 Cov.: 24 AF XY: 0.0271 AC XY: 12428 AN XY: 459408

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

African (AFR) AF: 0.0550 AC: 1187 AN: 21574

American (AMR) AF: 0.0302 AC: 876 AN: 28968

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 377 AN: 16140

East Asian (EAS) AF: 0.0186 AC: 450 AN: 24214

South Asian (SAS) AF: 0.0265 AC: 1462 AN: 55140

European-Finnish (FIN) AF: 0.0188 AC: 649 AN: 34494

Middle Eastern (MID) AF: 0.0174 AC: 73 AN: 4184

European-Non Finnish (NFE) AF: 0.0282 AC: 19772 AN: 700948

Other (OTH) AF: 0.0273 AC: 1033 AN: 37900

⚠️ 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: 0.00625 AC: 917 AN: 146694 Hom.: 7 Cov.: 32 AF XY: 0.00608 AC XY: 434 AN XY: 71338

African (AFR) AF: 0.0193 AC: 775 AN: 40226

American (AMR) AF: 0.00370 AC: 54 AN: 14576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

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

South Asian (SAS) AF: 0.000433 AC: 2 AN: 4616

European-Finnish (FIN) AF: 0.000213 AC: 2 AN: 9374

Middle Eastern (MID) AF: 0.00704 AC: 2 AN: 284

European-Non Finnish (NFE) AF: 0.00106 AC: 70 AN: 66280

Other (OTH) AF: 0.00446 AC: 9 AN: 2016

Alfa AF: 0.0290 Hom.: 0

Bravo AF: 0.00659

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.25
Mutation Taster		=100/0	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

dbSNP: rs371568839; hg19: chr1-210536178; COSMIC: COSV54810160; COSMIC: COSV54810160;