Genetic Variant TLCD1:p.Tyr197Phe (chr17-28724664-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_138463.4(TLCD1):c.590A>T(p.Tyr197Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TLCD1
NM_138463.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.15

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34527993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLCD1	NM_138463.4 link	c.590A>T	p.Tyr197Phe	missense_variant	Exon 4 of 4	ENST00000292090.8	NP_612472.1	Q96CP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TLCD1	ENST00000292090.8 link	c.590A>T	p.Tyr197Phe	missense_variant	Exon 4 of 4	1	NM_138463.4	ENSP00000292090.3	Q96CP7-1
TLCD1	ENST00000394933.7 link	c.449A>T	p.Tyr150Phe	missense_variant	Exon 4 of 4	2		ENSP00000378391.3	Q96CP7-2
TLCD1	ENST00000580518.1 link	c.377A>T	p.Tyr126Phe	missense_variant	Exon 4 of 4	3		ENSP00000466264.1	K7ELX5
TLCD1	ENST00000581236.1 link	c.111-11A>T		intron_variant	Intron 1 of 1	2		ENSP00000468670.1	K7ESD9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727230

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111976

Other (OTH)

AF:

0.00

AC:

AN:

60396

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.590A>T (p.Y197F) alteration is located in exon 4 (coding exon 4) of the TLCD1 gene. This alteration results from a A to T substitution at nucleotide position 590, causing the tyrosine (Y) at amino acid position 197 to be replaced by a phenylalanine (F). 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

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

T;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.72

T;T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.4

L;.;.

PhyloP100

4.2

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.9

N;N;.

REVEL

Uncertain

0.43

Sift

Benign

0.48

T;T;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

0.48

P;.;.

Vest4

0.40

MutPred

0.54

Gain of loop (P = 0.069);.;.;

MVP

0.37

MPC

0.45

ClinPred

0.71

GERP RS

5.8

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.087

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over