17-28725329-C-G

Variant names:

• chr17-28725329-C-G
• NM_138463.4:c.335G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_138463.4(TLCD1):​c.335G>C​(p.Trp112Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 6.70

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLCD1	NM_138463.4	c.335G>C	p.Trp112Ser	missense_variant	Exon 3 of 4	ENST00000292090.8	NP_612472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLCD1	ENST00000292090.8	c.335G>C	p.Trp112Ser	missense_variant	Exon 3 of 4	1	NM_138463.4	ENSP00000292090.3
TLCD1	ENST00000394933.7	c.194G>C	p.Trp65Ser	missense_variant	Exon 3 of 4	2		ENSP00000378391.3
TLCD1	ENST00000580518.1	c.122G>C	p.Trp41Ser	missense_variant	Exon 3 of 4	3		ENSP00000466264.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.335G>C (p.W112S) alteration is located in exon 3 (coding exon 3) of the TLCD1 gene. This alteration results from a G to C substitution at nucleotide position 335, causing the tryptophan (W) at amino acid position 112 to be replaced by a serine (S). 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	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.3	M;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-9.5	D;D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		0.98	D;.;.
Vest4		0.82
MutPred		0.82		Gain of disorder (P = 0);.;.;
MVP		0.75
MPC		1.6
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.75

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: chr17-27052347;