3-149324887-C-T

Position:

• chr3-149324887-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138786.4(TM4SF18):​c.403G>A​(p.Ala135Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TM4SF18 NM_138786.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.214

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0601812).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TM4SF18	NM_138786.4	c.403G>A	p.Ala135Thr	missense_variant	4/6	ENST00000296059.7	NP_620141.1
TM4SF18	NM_001184723.2	c.403G>A	p.Ala135Thr	missense_variant	3/5		NP_001171652.1
TM4SF18-AS1	NR_186251.1	n.405-8617C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TM4SF18	ENST00000296059.7	c.403G>A	p.Ala135Thr	missense_variant	4/6	1	NM_138786.4	ENSP00000296059.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The c.403G>A (p.A135T) alteration is located in exon 4 (coding exon 3) of the TM4SF18 gene. This alteration results from a G to A substitution at nucleotide position 403, causing the alanine (A) at amino acid position 135 to be replaced by a threonine (T). 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	0.078
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.90
DEOGEN2	Benign	0.017	T;T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.58	.;T;T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.060	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L;L;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.15	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.63	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.19
MutPred		0.40		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.13
MPC		0.12
ClinPred		0.053	T
GERP RS		1.3
Varity_R		0.026
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs1410724594; hg19: chr3-149042674;