11-865966-G-A

Position:

• chr11-865966-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003271.5(TSPAN4):​c.613G>A​(p.Val205Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,254 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSPAN4 NM_003271.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62

Genes affected

TSPAN4 (HGNC:11859): (tetraspanin 4) 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 glycoprotein and is similar in sequence to its family member CD53 antigen. It is known to complex with integrins and other transmembrane 4 superfamily proteins. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

TSPAN4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPAN4	NM_003271.5	c.613G>A	p.Val205Met	missense_variant	8/9	ENST00000397397.7	NP_003262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPAN4	ENST00000397397.7	c.613G>A	p.Val205Met	missense_variant	8/9	1	NM_003271.5	ENSP00000380552.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460254 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 726484

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.: 33

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

Feb 05, 2024

The c.613G>A (p.V205M) alteration is located in exon 8 (coding exon 6) of the TSPAN4 gene. This alteration results from a G to A substitution at nucleotide position 613, causing the valine (V) at amino acid position 205 to be replaced by a methionine (M). 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	Uncertain	0.34
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T;T;T;T;T;T;T;T;.
Eigen	Benign	-0.062
Eigen_PC	Benign	-0.053
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.92	.;.;D;D;.;.;.;.;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.50	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.057	D
MutationAssessor	Benign	1.5	L;L;.;L;L;L;.;L;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.079	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.11	T;T;T;T;T;T;T;T;T;T
Polyphen		0.42	B;B;.;B;B;B;.;B;.;.
Vest4		0.47
MutPred		0.47		Loss of catalytic residue at V205 (P = 0.0778);Loss of catalytic residue at V205 (P = 0.0778);.;Loss of catalytic residue at V205 (P = 0.0778);Loss of catalytic residue at V205 (P = 0.0778);Loss of catalytic residue at V205 (P = 0.0778);.;Loss of catalytic residue at V205 (P = 0.0778);.;.;
MVP		0.63
MPC		0.15
ClinPred		0.44	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.059
gMVP		0.72

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: chr11-865966;