17-28725973-G-A

Variant names:

• chr17-28725973-G-A
• rs2034219888
• NM_138463.4:c.125C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138463.4(TLCD1):​c.125C>T​(p.Thr42Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T42S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLCD1 NM_138463.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.95
• Publications: 0 publications found

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]

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: Ambry Genetics, ClinGen, G2P
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13879618).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138463.4. 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
	TLCD1	NM_138463.4	MANE Select	c.125C>T	p.Thr42Ile	missense	Exon 1 of 4	NP_612472.1	Q96CP7-1
	TLCD1	NM_001160407.2		c.54-410C>T		intron	N/A	NP_001153879.1	Q96CP7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLCD1	ENST00000292090.8	TSL:1 MANE Select	c.125C>T	p.Thr42Ile	missense	Exon 1 of 4	ENSP00000292090.3	Q96CP7-1
	NEK8	ENST00000579060.5	TSL:3	c.-101G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000466896.1	K7END4
	NEK8	ENST00000579060.5	TSL:3	c.-101G>A		5_prime_UTR	Exon 1 of 4	ENSP00000466896.1	K7END4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.0084	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.099
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.24
Sift	Benign	0.14	T
Sift4G	Uncertain	0.054	T
Polyphen		0.16	B
Vest4		0.32
MutPred		0.39		Gain of MoRF binding (P = 0.0815)
MVP		0.040
MPC		0.50
ClinPred		0.70	D
GERP RS		4.6
PromoterAI		0.15	Neutral
Varity_R		0.23
gMVP		0.24
Mutation Taster		=70/30	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: rs2034219888; hg19: chr17-27052991;