chr1-95191684-A-G

Variant names:

• chr1-95191684-A-G
• rs1175112724
• NM_152487.3:c.608A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152487.3(TLCD4):​c.608A>G​(p.Tyr203Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Y203F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLCD4 NM_152487.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.940
• Publications: 0 publications found

Genes affected

TLCD4 (HGNC:26477): (TLC domain containing 4) Predicted to be involved in lipid homeostasis. Predicted to be integral component of membrane. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

TLCD4-RWDD3 (HGNC:49388): (TLCD4-RWDD3 readthrough) This locus represents naturally occurring read-through transcription between the neighboring TMEM56 (transmembrane protein 56) and RWDD3 (RWD domain containing 3) genes on chromosome 1. The read-through transcript encodes a protein that shares sequence identity with the upstream gene product, but it contains a distinct C-terminus due to frameshifts versus the downstream gene coding sequence. [provided by RefSeq, Dec 2010]

RWDD3-DT (HGNC:55839): (RWDD3 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152487.3. 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
	TLCD4	NM_152487.3	MANE Select	c.608A>G	p.Tyr203Cys	missense	Exon 7 of 7	NP_689700.1	Q96MV1
	TLCD4	NM_001199679.2		c.608A>G	p.Tyr203Cys	missense	Exon 7 of 7	NP_001186608.1	Q96MV1
	TLCD4-RWDD3	NM_001199691.1		c.473+17795A>G		intron	N/A	NP_001186620.1	S4R434

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLCD4	ENST00000370203.9	TSL:1 MANE Select	c.608A>G	p.Tyr203Cys	missense	Exon 7 of 7	ENSP00000359222.4	Q96MV1
	TLCD4-RWDD3	ENST00000604534.5	TSL:2	c.473+17795A>G		intron	N/A	ENSP00000475025.1	S4R434
	TLCD4	ENST00000882686.1		c.608A>G	p.Tyr203Cys	missense	Exon 8 of 8	ENSP00000552745.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.0057	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	0.056
Eigen_PC	Benign	-0.078
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.94
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.022	D
Polyphen		0.99	D
Vest4		0.26
MutPred		0.58		Loss of sheet (P = 0.0181)
MVP		0.76
MPC		1.0
ClinPred		0.95	D
GERP RS		0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.60
Mutation Taster		=87/13	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: rs1175112724; hg19: chr1-95657240;