17-28724809-T-C

Position:

• chr17-28724809-T-C

Variant summary

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

The NM_138463.4(TLCD1):​c.445A>G​(p.Ile149Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TLCD1 NM_138463.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20

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=0.37858742).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLCD1	NM_138463.4	c.445A>G	p.Ile149Val	missense_variant	4/4	ENST00000292090.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLCD1	ENST00000292090.8	c.445A>G	p.Ile149Val	missense_variant	4/4	1	NM_138463.4	P1
TLCD1	ENST00000394933.7	c.304A>G	p.Ile102Val	missense_variant	4/4	2
TLCD1	ENST00000580518.1	c.232A>G	p.Ile78Val	missense_variant	4/4	3
TLCD1	ENST00000581236.1	c.43A>G	p.Ile15Val	missense_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2023

The c.445A>G (p.I149V) alteration is located in exon 4 (coding exon 4) of the TLCD1 gene. This alteration results from a A to G substitution at nucleotide position 445, causing the isoleucine (I) at amino acid position 149 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	0.18
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.72	N;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.51	N;N;.
REVEL	Uncertain	0.35
Sift	Benign	0.34	T;T;.
Sift4G	Pathogenic	0.0	D;T;.
Polyphen		0.81	P;.;.
Vest4		0.072
MutPred		0.64		Gain of catalytic residue at I149 (P = 0.1475);.;.;
MVP		0.39
MPC		0.91
ClinPred		0.51	D
GERP RS		5.9
Varity_R		0.089
gMVP		0.23

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: chr17-27051827;