17-28726757-T-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001160407.2(TLCD1):c.52A>C(p.Ser18Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00045 in 1,549,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 0 hom. )

Consequence

TLCD1
NM_001160407.2 missense, splice_region

Scores

Splicing: ADA: 0.0001130

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.252

Publications

3 publications found

Variant links:

Genes affected

TLCD1 (HGNC:25177): (TLC domain containing 1) Involved in several processes, including membrane assembly; phospholipid homeostasis; and regulation of membrane lipid distribution. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TLCD1 links:

NEK8 (HGNC:13387): (NIMA related kinase 8) This gene encodes a member of the serine/threionine protein kinase family related to NIMA (never in mitosis, gene A) of Aspergillus nidulans. The encoded protein may play a role in cell cycle progression from G2 to M phase. Mutations in the related mouse gene are associated with a disease phenotype that closely parallels the juvenile autosomal recessive form of polycystic kidney disease in humans. [provided by RefSeq, Jul 2008]

NEK8 Gene-Disease associations (from GenCC):

renal-hepatic-pancreatic dysplasia 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Ambry Genetics
autosomal dominant polycystic kidney disease
Inheritance: AD Classification: STRONG Submitted by: ClinGen
nephronophthisis 9
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
polycystic kidney disease 8
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
nephronophthisis 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
renal-hepatic-pancreatic dysplasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NEK8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1431936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
TLCD1	NM_001160407.2 link	c.52A>C	p.Ser18Arg	missense_variant, splice_region_variant	Exon 1 of 4	NP_001153879.1	Q96CP7-2
TLCD1	XM_047435299.1 link	c.52A>C	p.Ser18Arg	missense_variant, splice_region_variant	Exon 1 of 5	XP_047291255.1
TLCD1	XM_006721671.5 link	c.-20+1062A>C		intron_variant	Intron 1 of 3	XP_006721734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
TLCD1	ENST00000394933.7 link	c.52A>C	p.Ser18Arg	missense_variant, splice_region_variant	Exon 1 of 4	2	ENSP00000378391.3	Q96CP7-2
NEK8	ENST00000579060.5 link	c.-71+754T>G		intron_variant	Intron 1 of 3	3	ENSP00000466896.1	K7END4
NEK8	ENST00000579671.5 link	c.-71+785T>G		intron_variant	Intron 1 of 3	3	ENSP00000467335.1	K7EPD3

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000309

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000240

AC:

AN:

154338

AF XY:

0.000280

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000549

Gnomad OTH exome

AF:

0.000457

GnomAD4 exome

AF:

0.000479

AC:

669

AN:

1396892

Hom.:

Cov.:

AF XY:

0.000472

AC XY:

325

AN XY:

689120

show subpopulations

African (AFR)

AF:

0.0000950

AC:

AN:

31594

American (AMR)

AF:

0.0000560

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25174

East Asian (EAS)

AF:

0.00

AC:

AN:

35730

South Asian (SAS)

AF:

0.00

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.0000213

AC:

AN:

46950

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.000607

AC:

655

AN:

1078834

Other (OTH)

AF:

0.000138

AC:

AN:

57972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

131

164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000184

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41570

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000298

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000155

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 23, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.52A>C (p.S18R) alteration is located in exon 1 (coding exon 1) of the TLCD1 gene. This alteration results from a A to C substitution at nucleotide position 52, causing the serine (S) at amino acid position 18 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.28

CADD

Benign

5.3

(source)

DANN

Benign

0.91

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.31

M_CAP

Benign

0.011

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.96

PhyloP100

-0.25

PROVEAN

Benign

-0.52

REVEL

Benign

0.035

Sift

Uncertain

0.017

Sift4G

Pathogenic

0.0

Vest4

0.55

MutPred

0.46

Gain of MoRF binding (P = 0.0244);

MVP

0.030

ClinPred

0.016

GERP RS

-1.9

PromoterAI

0.15

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.072

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

Publications

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17-28726757-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over