1-95191650-A-T

Variant names:

• chr1-95191650-A-T
• rs770980987
• NM_152487.3:c.574A>T

Variant summary

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

The NM_152487.3(TLCD4):​c.574A>T​(p.Met192Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. M192V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TLCD4 NM_152487.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.08
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27866596).

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.574A>T	p.Met192Leu	missense	Exon 7 of 7	NP_689700.1	Q96MV1
	TLCD4	NM_001199679.2		c.574A>T	p.Met192Leu	missense	Exon 7 of 7	NP_001186608.1	Q96MV1
	TLCD4-RWDD3	NM_001199691.1		c.473+17761A>T		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.574A>T	p.Met192Leu	missense	Exon 7 of 7	ENSP00000359222.4	Q96MV1
	TLCD4-RWDD3	ENST00000604534.5	TSL:2	c.473+17761A>T		intron	N/A	ENSP00000475025.1	S4R434
	TLCD4	ENST00000882686.1		c.574A>T	p.Met192Leu	missense	Exon 8 of 8	ENSP00000552745.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727226

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: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

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	0.20
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	17
DANN	Benign	0.60
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.12
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.0	L
PhyloP100		9.1
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.20	N
REVEL	Uncertain	0.36
Sift	Benign	0.14	T
Sift4G	Benign	0.54	T
Polyphen		0.0040	B
Vest4		0.30
MutPred		0.62		Gain of helix (P = 0.0425)
MVP		0.34
MPC		0.29
ClinPred		0.72	D
GERP RS		5.9
Varity_R		0.20
gMVP		0.61
Mutation Taster		=41/59	disease causing

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: rs770980987; hg19: chr1-95657206;