3-149330347-A-C

Variant names:

• chr3-149330347-A-C
• NM_138786.4:c.250T>G

Variant summary

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

The NM_138786.4(TM4SF18):​c.250T>G​(p.Cys84Gly) 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: TM4SF18 NM_138786.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.87

Genes affected

TM4SF18 (HGNC:25181): (transmembrane 4 L six family member 18) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TM4SF18-AS1 (HGNC:56678): (TM4SF18 antisense RNA 1)

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, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM4SF18	NM_138786.4	c.250T>G	p.Cys84Gly	missense_variant	Exon 3 of 6	ENST00000296059.7	NP_620141.1
TM4SF18	NM_001184723.2	c.250T>G	p.Cys84Gly	missense_variant	Exon 2 of 5		NP_001171652.1
TM4SF18-AS1	NR_186251.1	n.405-3157A>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TM4SF18	ENST00000296059.7	c.250T>G	p.Cys84Gly	missense_variant	Exon 3 of 6	1	NM_138786.4	ENSP00000296059.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.250T>G (p.C84G) alteration is located in exon 3 (coding exon 2) of the TM4SF18 gene. This alteration results from a T to G substitution at nucleotide position 250, causing the cysteine (C) at amino acid position 84 to be replaced by a glycine (G). 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	Benign	0.11
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.36	T;T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	.;T;T
M_CAP	Benign	0.0082	T
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Pathogenic	2.9	M;M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-8.5	D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0080	D;D;D
Sift4G	Benign	0.081	T;T;.
Polyphen		1.0	D;D;.
Vest4		0.87
MutPred		0.86		Gain of disorder (P = 0.003);Gain of disorder (P = 0.003);Gain of disorder (P = 0.003);
MVP		0.61
MPC		0.63
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.58
gMVP		0.74

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: chr3-149048134;