4-182324138-T-A

Position:

• chr4-182324138-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001080477.4(TENM3):​c.118T>A​(p.Ser40Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TENM3 NM_001080477.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

Genes affected

TENM3 (HGNC:29944): (teneurin transmembrane protein 3) This gene encodes a member of the teneurin transmembrane protein family. The encoded protein may be involved in the regulation of neuronal development including development of the visual pathway. Mutations in this gene have been associated with microphthalmia and developmental dysplasia of the hip. [provided by RefSeq, Jan 2023]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TENM3. . Gene score misZ 3.2996 (greater than the threshold 3.09). Trascript score misZ 3.8249 (greater than threshold 3.09). GenCC has associacion of gene with microphthalmia, isolated, with coloboma, microphthalmia, isolated, with coloboma 9.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TENM3	NM_001080477.4	c.118T>A	p.Ser40Thr	missense_variant	2/28	ENST00000511685.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TENM3	ENST00000511685.6	c.118T>A	p.Ser40Thr	missense_variant	2/28	5	NM_001080477.4	P1
TENM3	ENST00000513201.1	n.368T>A		non_coding_transcript_exon_variant	2/4	1
TENM3	ENST00000512480.5	c.118T>A	p.Ser40Thr	missense_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2023

The c.118T>A (p.S40T) alteration is located in exon 1 (coding exon 1) of the TENM3 gene. This alteration results from a T to A substitution at nucleotide position 118, causing the serine (S) at amino acid position 40 to be replaced by a threonine (T). 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	0.38
BayesDel_addAF	Benign	0.0035	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.087	.;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.8	.;L
MutationTaster	Benign	0.99	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.6	D;N
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.032	D;D
Polyphen		0.99	D;D
Vest4		0.61
MutPred		0.64		Gain of glycosylation at Y41 (P = 0.0103);Gain of glycosylation at Y41 (P = 0.0103);
MVP		0.21
MPC		0.47
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.37
gMVP		0.69

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: chr4-183245291;