3-149322362-A-G

Position:

• chr3-149322362-A-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.485T>C​(p.Phe162Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TM4SF18 NM_138786.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.75

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:):

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, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TM4SF18	NM_138786.4	c.485T>C	p.Phe162Ser	missense_variant	5/6	ENST00000296059.7	NP_620141.1
TM4SF18	NM_001184723.2	c.485T>C	p.Phe162Ser	missense_variant	4/5		NP_001171652.1
TM4SF18-AS1	NR_186251.1	n.405-11142A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TM4SF18	ENST00000296059.7	c.485T>C	p.Phe162Ser	missense_variant	5/6	1	NM_138786.4	ENSP00000296059.2
TM4SF18	ENST00000470080.5	c.485T>C	p.Phe162Ser	missense_variant	4/5	2		ENSP00000419278.1
TM4SF18-AS1	ENST00000489011.1	n.402-11142A>G		intron_variant		4
TM4SF18	ENST00000474754.1	c.*6T>C		downstream_gene_variant		2		ENSP00000418372.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461766 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

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: 8.99e-7

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

Apr 20, 2023

The c.485T>C (p.F162S) alteration is located in exon 5 (coding exon 4) of the TM4SF18 gene. This alteration results from a T to C substitution at nucleotide position 485, causing the phenylalanine (F) at amino acid position 162 to be replaced by a serine (S). 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	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	.;T
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	3.3	M;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.075	T;T
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.86		Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);
MVP		0.82
MPC		0.74
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.93

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: rs1559989675; hg19: chr3-149040149;