chr4-182346801-C-T

Variant names:

• chr4-182346801-C-T
• NM_001080477.4:c.383C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001080477.4(TENM3):​c.383C>T​(p.Pro128Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TENM3 NM_001080477.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

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]

TENM3 Gene-Disease associations (from GenCC):

• microphthalmia, isolated, with coloboma 9

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia
• microphthalmia, isolated, with coloboma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080477.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TENM3	NM_001080477.4	MANE Select	c.383C>T	p.Pro128Leu	missense	Exon 3 of 28	NP_001073946.1	Q9P273
	TENM3	NM_001415969.1		c.383C>T	p.Pro128Leu	missense	Exon 3 of 29	NP_001402898.1
	TENM3	NM_001415970.1		c.383C>T	p.Pro128Leu	missense	Exon 3 of 29	NP_001402899.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TENM3	ENST00000511685.6	TSL:5 MANE Select	c.383C>T	p.Pro128Leu	missense	Exon 3 of 28	ENSP00000424226.1	Q9P273
	TENM3	ENST00000513201.1	TSL:1	n.633C>T		non_coding_transcript_exon	Exon 3 of 4
	TENM3	ENST00000851056.1		c.383C>T	p.Pro128Leu	missense	Exon 3 of 31	ENSP00000521125.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-8.4	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.89		Loss of disorder (P = 0.052)
MVP		0.25
MPC		0.88
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.42
gMVP		0.65
Mutation Taster		=38/62	disease causing

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: chr4-183267954;