chr3-149377525-C-A

Variant names:

• chr3-149377525-C-A
• rs376614051
• NM_014220.3:c.23G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014220.3(TM4SF1):​c.23G>T​(p.Arg8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R8Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TM4SF1 NM_014220.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.81

Genes affected

TM4SF1 (HGNC:11853): (transmembrane 4 L six family member 1) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface antigen and is highly expressed in different carcinomas. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM4SF1	NM_014220.3	c.23G>T	p.Arg8Leu	missense_variant	Exon 1 of 5	ENST00000305366.8	NP_055035.1
TM4SF1	NM_001410837.1	c.23G>T	p.Arg8Leu	missense_variant	Exon 1 of 3		NP_001397766.1
TM4SF1	XM_017006385.3	c.23G>T	p.Arg8Leu	missense_variant	Exon 1 of 5		XP_016861874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TM4SF1	ENST00000305366.8	c.23G>T	p.Arg8Leu	missense_variant	Exon 1 of 5	1	NM_014220.3	ENSP00000304277.3
TM4SF1	ENST00000493298.1	n.23G>T		non_coding_transcript_exon_variant	Exon 1 of 3	4		ENSP00000418025.1
TM4SF1	ENST00000493348.1	n.23G>T		non_coding_transcript_exon_variant	Exon 1 of 4	2		ENSP00000419426.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.049
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.30
Sift	Benign	0.059	T
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.84		Loss of glycosylation at S13 (P = 0.0171);
MVP		0.33
MPC		0.34
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.35
gMVP		0.85

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: rs376614051; hg19: chr3-149095312;