Genetic Variant TTC6:p.Ala1659fs (chr14-37826179-TGGAAAATTATTTTAGGCCCAA-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PVS1_ModerateBP6_ModerateBS2

The ENST00000553443.6(TTC6):c.4975-15_4980delGGAAAATTATTTTAGGCCCAA(p.Ala1659_Gly1661del) variant causes a splice acceptor, conservative inframe deletion, splice region, intron change. The variant allele was found at a frequency of 0.00517 in 1,586,596 control chromosomes in the GnomAD database, including 33 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0035 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 28 hom. )

Consequence

TTC6
ENST00000553443.6 splice_acceptor, conservative_inframe_deletion, splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.94

Variant links:

Genes affected

TTC6 (HGNC:19739): (tetratricopeptide repeat domain 6)

TTC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.027027028 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.8, offset of 28, new splice context is: ccactttaccattgccatAGata. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BP6

Variant 14-37826179-TGGAAAATTATTTTAGGCCCAA-T is Benign according to our data. Variant chr14-37826179-TGGAAAATTATTTTAGGCCCAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 2644187.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC6	NM_001310135.5 link	c.4975-7_4988delATTTTAGGCCCAAGGAAAATT	p.Ala1659fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 30 of 33	ENST00000553443.6	NP_001297064.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC6	ENST00000553443.6 link	c.4975-15_4980delGGAAAATTATTTTAGGCCCAA	p.Ala1659_Gly1661del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 30 of 33	5	NM_001310135.5	ENSP00000451131.1		G3V3A5

Frequencies

GnomAD3 genomes

AF:

0.00352

AC:

535

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00184

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00330

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00606

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00363

AC:

819

AN:

225896

AF XY:

0.00368

show subpopulations

Gnomad AFR exome

AF:

0.00133

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.000842

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00236

Gnomad NFE exome

AF:

0.00615

Gnomad OTH exome

AF:

0.00484

GnomAD4 exome

AF:

0.00534

AC:

7662

AN:

1434420

Hom.:

AF XY:

0.00521

AC XY:

3713

AN XY:

713270

show subpopulations

Gnomad4 AFR exome

AF:

0.000844

AC:

AN:

31972

Gnomad4 AMR exome

AF:

0.00197

AC:

AN:

38164

Gnomad4 ASJ exome

AF:

0.000733

AC:

AN:

24542

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39406

Gnomad4 SAS exome

AF:

0.00136

AC:

111

AN:

81650

Gnomad4 FIN exome

AF:

0.00228

AC:

120

AN:

52692

Gnomad4 NFE exome

AF:

0.00634

AC:

6986

AN:

1101388

Gnomad4 Remaining exome

AF:

0.00478

AC:

282

AN:

59032

Heterozygous variant carriers

333

666

999

1332

1665

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

258

516

774

1032

1290

<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:

0.00352

AC:

535

AN:

152176

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

233

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.00116

AC:

0.00115523

AN:

0.00115523

Gnomad4 AMR

AF:

0.00184

AC:

0.00183582

AN:

0.00183582

Gnomad4 ASJ

AF:

0.000288

AC:

0.000288351

AN:

0.000288351

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00145

AC:

0.00145168

AN:

0.00145168

Gnomad4 FIN

AF:

0.00330

AC:

0.00329815

AN:

0.00329815

Gnomad4 NFE

AF:

0.00606

AC:

0.00606114

AN:

0.00606114

Gnomad4 OTH

AF:

0.00142

AC:

0.0014218

AN:

0.0014218

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

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

Alfa

AF:

0.00487

Hom.:

Bravo

AF:

0.00344

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTC6: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=139/61

disease causing (fs/PTC)

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over