17-28724866-A-C

Variant names:

• chr17-28724866-A-C
• NM_138463.4:c.388T>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_138463.4(TLCD1):​c.388T>G​(p.Phe130Val) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLCD1 NM_138463.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.87

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34358144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLCD1	NM_138463.4	c.388T>G	p.Phe130Val	missense_variant	Exon 4 of 4	ENST00000292090.8	NP_612472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLCD1	ENST00000292090.8	c.388T>G	p.Phe130Val	missense_variant	Exon 4 of 4	1	NM_138463.4	ENSP00000292090.3
TLCD1	ENST00000394933.7	c.247T>G	p.Phe83Val	missense_variant	Exon 4 of 4	2		ENSP00000378391.3
TLCD1	ENST00000580518.1	c.175T>G	p.Phe59Val	missense_variant	Exon 4 of 4	3		ENSP00000466264.1
TLCD1	ENST00000581236.1	c.-18T>G		upstream_gene_variant		2		ENSP00000468670.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.388T>G (p.F130V) alteration is located in exon 4 (coding exon 4) of the TLCD1 gene. This alteration results from a T to G substitution at nucleotide position 388, causing the phenylalanine (F) at amino acid position 130 to be replaced by a valine (V). 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	0.27
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.63	T;T;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.0	L;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N;N;.
REVEL	Uncertain	0.42
Sift	Benign	0.50	T;T;.
Sift4G	Uncertain	0.039	D;T;.
Polyphen		0.18	B;.;.
Vest4		0.51
MutPred		0.72		Loss of helix (P = 0.1299);.;.;
MVP		0.58
MPC		0.74
ClinPred		0.48	T
GERP RS		5.9
Varity_R		0.091
gMVP		0.59

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-27051884;