16-30029469-T-C

Variant names:

• chr16-30029469-T-C
• rs778788645
• NM_031478.6:c.172A>G

Variant summary

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

The NM_031478.6(TLCD3B):​c.172A>G​(p.Ile58Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,174 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. I58L) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TLCD3B NM_031478.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.49
• Publications: 0 publications found

Genes affected

TLCD3B (HGNC:25295): (TLC domain containing 3B) This gene encodes a transmembrane protein, which may be a likely target of peroxisome proliferator-activated receptor gamma (PPAR-gamma). The product of the orthologous gene in mouse is related to obesity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

TLCD3B Gene-Disease associations (from GenCC):

• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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=0.35987216).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031478.6. 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
	TLCD3B	NM_031478.6	MANE Select	c.172A>G	p.Ile58Val	missense	Exon 2 of 5	NP_113666.2	Q71RH2-1
	TLCD3B	NM_001352173.2		c.430A>G	p.Ile144Val	missense	Exon 3 of 6	NP_001339102.1
	TLCD3B	NM_001318504.2		c.22A>G	p.Ile8Val	missense	Exon 2 of 5	NP_001305433.1	Q71RH2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLCD3B	ENST00000380495.9	TSL:1 MANE Select	c.172A>G	p.Ile58Val	missense	Exon 2 of 5	ENSP00000369863.4	Q71RH2-1
	TLCD3B	ENST00000279389.8	TSL:1	c.22A>G	p.Ile8Val	missense	Exon 2 of 5	ENSP00000279389.4	Q71RH2-2
	TLCD3B	ENST00000934494.1		c.172A>G	p.Ile58Val	missense	Exon 2 of 5	ENSP00000604553.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.093
Eigen_PC	Benign	0.078
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.23	N
REVEL	Uncertain	0.33
Sift	Benign	0.41	T
Sift4G	Benign	0.47	T
Polyphen		0.0040	B
Vest4		0.30
MutPred		0.47		Gain of glycosylation at S60 (P = 0.1249)
MVP		0.68
MPC		0.44
ClinPred		0.63	D
GERP RS		4.9
PromoterAI		0.038	Neutral
Varity_R		0.13
gMVP		0.37

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: rs778788645; hg19: chr16-30040790;