4-98658193-T-C

Variant names:

• chr4-98658193-T-C
• NM_005723.4:c.34A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005723.4(TSPAN5):​c.34A>G​(p.Ser12Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSPAN5 NM_005723.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.58
• Publications: 0 publications found

Genes affected

TSPAN5 (HGNC:17753): (tetraspanin 5) 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. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3009704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN5	NM_005723.4	c.34A>G	p.Ser12Gly	missense_variant	Exon 1 of 8	ENST00000305798.8	NP_005714.2
TSPAN5	XM_005262680.2	c.34A>G	p.Ser12Gly	missense_variant	Exon 1 of 7		XP_005262737.1
TSPAN5	XM_047449476.1	c.34A>G	p.Ser12Gly	missense_variant	Exon 1 of 7		XP_047305432.1
TSPAN5	XM_047449477.1	c.34A>G	p.Ser12Gly	missense_variant	Exon 1 of 6		XP_047305433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPAN5	ENST00000305798.8	c.34A>G	p.Ser12Gly	missense_variant	Exon 1 of 8	1	NM_005723.4	ENSP00000307701.3
TSPAN5	ENST00000507167.1	n.102A>G		non_coding_transcript_exon_variant	Exon 1 of 3	2
TSPAN5	ENST00000508798.5	n.34A>G		non_coding_transcript_exon_variant	Exon 1 of 8	5		ENSP00000421808.1
TSPAN5	ENST00000515440.5	n.4A>G		non_coding_transcript_exon_variant	Exon 1 of 6	3		ENSP00000422351.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34A>G (p.S12G) alteration is located in exon 1 (coding exon 1) of the TSPAN5 gene. This alteration results from a A to G substitution at nucleotide position 34, causing the serine (S) at amino acid position 12 to be replaced by a glycine (G). 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	0.15
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		6.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.11
Sift	Benign	0.16	T
Sift4G	Uncertain	0.059	T
Polyphen		0.029	B
Vest4		0.60
MutPred		0.46		Loss of glycosylation at S12 (P = 0.0252);
MVP		0.068
MPC		0.89
ClinPred		0.84	D
GERP RS		3.0
PromoterAI		0.082	Neutral
Varity_R		0.24
gMVP		0.66
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

hg19: chr4-99579344;