chr17-28725357-C-G

Variant names:

• chr17-28725357-C-G
• rs150163733
• NM_138463.4:c.307G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_138463.4(TLCD1):​c.307G>C​(p.Val103Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. V103M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TLCD1 NM_138463.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41
• 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]

ACMG classification

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=0.27838808).

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.307G>C	p.Val103Leu	missense	Exon 3 of 4	NP_612472.1	Q96CP7-1
	TLCD1	NM_001160407.2		c.166G>C	p.Val56Leu	missense	Exon 3 of 4	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.307G>C	p.Val103Leu	missense	Exon 3 of 4	ENSP00000292090.3	Q96CP7-1
	TLCD1	ENST00000394933.7	TSL:2	c.166G>C	p.Val56Leu	missense	Exon 3 of 4	ENSP00000378391.3	Q96CP7-2
	TLCD1	ENST00000580518.1	TSL:3	c.94G>C	p.Val32Leu	missense	Exon 3 of 4	ENSP00000466264.1	K7ELX5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.010	N
REVEL	Uncertain	0.33
Sift	Benign	0.42	T
Sift4G	Benign	0.13	T
Polyphen		0.059	B
Vest4		0.19
MutPred		0.50		Loss of catalytic residue at V103 (P = 0.0492)
MVP		0.61
MPC		0.41
ClinPred		0.50	T
GERP RS		4.6
Varity_R		0.059
gMVP		0.40
Mutation Taster		=78/22	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: rs150163733; hg19: chr17-27052375;