17-28724624-G-C

Position:

• chr17-28724624-G-C

Variant summary

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

The NM_138463.4(TLCD1):​c.630C>G​(p.Ile210Met) 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. 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: 3.30

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=0.4228841).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLCD1	NM_138463.4	c.630C>G	p.Ile210Met	missense_variant	4/4	ENST00000292090.8	NP_612472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLCD1	ENST00000292090.8	c.630C>G	p.Ile210Met	missense_variant	4/4	1	NM_138463.4	ENSP00000292090	P1
TLCD1	ENST00000394933.7	c.489C>G	p.Ile163Met	missense_variant	4/4	2		ENSP00000378391
TLCD1	ENST00000580518.1	c.417C>G	p.Ile139Met	missense_variant	4/4	3		ENSP00000466264
TLCD1	ENST00000581236.1	c.143C>G	p.Ser48Cys	missense_variant	2/2	2		ENSP00000468670

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2024

The c.630C>G (p.I210M) alteration is located in exon 4 (coding exon 4) of the TLCD1 gene. This alteration results from a C to G substitution at nucleotide position 630, causing the isoleucine (I) at amino acid position 210 to be replaced by a methionine (M). 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	0.15
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	12
DANN	Benign	0.91
DEOGEN2	Benign	0.34	T;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.42	T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	0.71	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.31	N;N;.
REVEL	Uncertain	0.34
Sift	Benign	0.086	T;T;.
Sift4G	Benign	0.12	T;T;.
Polyphen		0.070	B;.;.
Vest4		0.29
MutPred		0.64		Loss of stability (P = 0.1528);.;.;
MVP		0.46
MPC		0.87
ClinPred		0.32	T
GERP RS		3.5
Varity_R		0.057
gMVP		0.30

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: chr17-27051642; COSMIC: COSV52046481; COSMIC: COSV52046481;