NM_138786.4:c.266T>G

Variant names:

• chr3-149330331-A-C
• rs980558961
• NM_138786.4:c.266T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138786.4(TM4SF18):​c.266T>G​(p.Val89Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,609,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TM4SF18 NM_138786.4 missense, splice_region
• Scores: Splicing: ADA: 0.00005834
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.320
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07349646).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138786.4. 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
	TM4SF18	NM_138786.4	MANE Select	c.266T>G	p.Val89Gly	missense splice_region	Exon 3 of 6	NP_620141.1	Q96CE8
	TM4SF18	NM_001184723.2		c.266T>G	p.Val89Gly	missense splice_region	Exon 2 of 5	NP_001171652.1	Q96CE8
	TM4SF18-AS1	NR_186251.1		n.405-3173A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM4SF18	ENST00000296059.7	TSL:1 MANE Select	c.266T>G	p.Val89Gly	missense splice_region	Exon 3 of 6	ENSP00000296059.2	Q96CE8
	TM4SF18	ENST00000470080.5	TSL:2	c.266T>G	p.Val89Gly	missense splice_region	Exon 2 of 5	ENSP00000419278.1	Q96CE8
	TM4SF18	ENST00000855970.1		c.266T>G	p.Val89Gly	missense splice_region	Exon 3 of 6	ENSP00000526029.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249136 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456992 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 724916

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.0000225 AC: 1 AN: 44398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108666

Other (OTH) AF: 0.0000166 AC: 1 AN: 60176

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0338994), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.000131 AC: 2 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	6.2
DANN	Benign	0.93
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.55	N
PhyloP100		0.32
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.20
Sift	Benign	0.27	T
Sift4G	Benign	0.23	T
Polyphen		0.010	B
Vest4		0.37
MutPred		0.61		Gain of disorder (P = 0.0309)
MVP		0.13
MPC		0.18
ClinPred		0.11	T
GERP RS		-4.5
Varity_R		0.076
gMVP		0.49
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000058
dbscSNV1_RF	Benign	0.0
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: rs980558961; hg19: chr3-149048118;