Genetic Variant HHAT:c.92-8_92-7delTT (chr1-210362834-CTT-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_018194.6(HHAT):c.92-8_92-7delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000067 in 1,208,428 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as (no stars).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

HHAT
NM_018194.6 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.178

Publications

0 publications found

Variant links:

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)

HHAT links:

ENSG00000287354 (HGNC:):

ENSG00000287354 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HHAT	NM_018194.6	MANE Select	c.92-8_92-7delTT	splice_region intron	N/A	NP_060664.2	Q5VTY9-1
HHAT	NM_001170587.3		c.95-8_95-7delTT	splice_region intron	N/A	NP_001164058.1	Q5VTY9-7
HHAT	NM_001122834.4		c.92-8_92-7delTT	splice_region intron	N/A	NP_001116306.1	Q5VTY9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HHAT	ENST00000261458.8	TSL:2 MANE Select	c.92-17_92-16delTT	intron	N/A	ENSP00000261458.3	Q5VTY9-1
HHAT	ENST00000545154.5	TSL:2	c.95-17_95-16delTT	intron	N/A	ENSP00000438468.1	Q5VTY9-7
HHAT	ENST00000367010.5	TSL:2	c.92-17_92-16delTT	intron	N/A	ENSP00000355977.1	Q5VTY9-1

Frequencies

GnomAD3 genomes

AF:

0.0000136

AC:

AN:

146704

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000302

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000255

AC:

AN:

82276

AF XY:

0.000274

show subpopulations

Gnomad AFR exome

AF:

0.000171

Gnomad AMR exome

AF:

0.000380

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000698

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.000257

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000744

AC:

AN:

1061724

Hom.:

AF XY:

0.0000641

AC XY:

AN XY:

530026

show subpopulations

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

African (AFR)

AF:

0.0000809

AC:

AN:

24722

American (AMR)

AF:

0.000179

AC:

AN:

33482

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18996

East Asian (EAS)

AF:

0.00

AC:

AN:

28898

South Asian (SAS)

AF:

0.0000772

AC:

AN:

64766

European-Finnish (FIN)

AF:

0.0000760

AC:

AN:

39488

Middle Eastern (MID)

AF:

0.000437

AC:

AN:

4574

European-Non Finnish (NFE)

AF:

0.0000747

AC:

AN:

802836

Other (OTH)

AF:

0.0000227

AC:

AN:

43962

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.298

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000136

AC:

AN:

146704

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40150

American (AMR)

AF:

0.00

AC:

AN:

14572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3384

East Asian (EAS)

AF:

0.00

AC:

AN:

5052

South Asian (SAS)

AF:

0.00

AC:

AN:

4626

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000302

AC:

AN:

66322

Other (OTH)

AF:

0.00

AC:

AN:

1998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000984

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.26

Position offset: 18

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

Publications

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1-210362834-CTTT-CT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over