17-40478583-C-G

Variant names:

• chr17-40478583-C-G
• rs145753216
• NM_032865.6:c.1976G>C

Variant summary

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

The NM_032865.6(TNS4):​c.1976G>C​(p.Arg659Pro) variant causes a missense change involving the alteration of a 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. R659Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNS4 NM_032865.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.86

Genes affected

TNS4 (HGNC:24352): (tensin 4) Predicted to enable actin binding activity. Involved in protein localization. Located in focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNS4	NM_032865.6	c.1976G>C	p.Arg659Pro	missense_variant	Exon 11 of 13	ENST00000254051.11	NP_116254.4
TNS4	XM_047436949.1	c.2312G>C	p.Arg771Pro	missense_variant	Exon 11 of 13		XP_047292905.1
TNS4	XM_005257744.2	c.1973G>C	p.Arg658Pro	missense_variant	Exon 11 of 13		XP_005257801.1
TNS4	XM_017025236.2	c.1898G>C	p.Arg633Pro	missense_variant	Exon 10 of 12		XP_016880725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNS4	ENST00000254051.11	c.1976G>C	p.Arg659Pro	missense_variant	Exon 11 of 13	1	NM_032865.6	ENSP00000254051.6
TNS4	ENST00000394072.7	n.242G>C		non_coding_transcript_exon_variant	Exon 2 of 4	1
TNS4	ENST00000582747.1	c.65G>C	p.Arg22Pro	missense_variant	Exon 1 of 2	3		ENSP00000463456.1
TNS4	ENST00000497303.1	n.405G>C		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.10	T
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.61		Loss of MoRF binding (P = 0.0092);
MVP		0.87
MPC		0.78
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.89
gMVP		0.75

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: rs145753216; hg19: chr17-38634835;